JP7472190B2 - Methods of Treating Cancer with Anti-TIM-3 Antibodies - Google Patents

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62/444,354, filed January 9, 2017, and U.S. Provisional Application No. 62/582,272, filed November 6, 2017, each of which is incorporated by reference in its entirety.
SEQUENCE LISTING This specification refers to a Sequence Listing, which is provided in electronic form as an ASCII.txt file entitled "TSR-002 SEQ LIST_ST25" (created on January 8, 2018, size 39,647 bytes).

Cancer is a major public health problem, and according to the American Cancer Society, Cancer Facts & Figures 2017 (https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2017.html), approximately 600,920 people are expected to die from cancer in the United States in 2017 alone. Thus, there is a continuing need for effective therapies to treat cancer patients.

American Cancer Society, Cancer Facts & Figures 2017 (https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2017.html)

The present invention encompasses the recognition that certain dosing regimens for agents capable of inhibiting T cell immunoglobulin and mucin domain-3 (TIM-3) signaling (e.g., anti-TIM-3 antibody agents) are useful in treating disorders such as cancer.

In some embodiments, the disclosure provides a method of treating a disorder, such as cancer, comprising administering a composition that delivers a specific TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) according to a dosing regimen that can achieve clinical benefit in at least some patients.

In embodiments, the TIM-3 inhibitor is a TIM-3 binding agent. In embodiments, the TIM-3 binding agent is an antibody, antibody conjugate, or antigen-binding fragment thereof. In embodiments, the TIM-3 binding agent is an antibody drug (i.e., an anti-TIM-3 antibody drug).

In embodiments, the anti-TIM-3 antibody agent comprises a heavy chain variable region comprising one or more CDR sequences selected from SEQ ID NOs: 21, 22, and 23, and/or a light chain variable region comprising one or more CDR sequences selected from SEQ ID NOs: 24, 25, and 26. In embodiments, the anti-TIM-3 antibody agent comprises a heavy chain variable region comprising two or three CDR sequences selected from SEQ ID NOs: 21, 22, and 23, and/or a light chain variable region comprising two or three CDR sequences selected from SEQ ID NOs: 24, 25, and 26. In embodiments, the anti-TIM-3 antibody agent comprises a heavy chain variable region comprising the three CDR sequences of SEQ ID NOs: 21, 22, and 23, and/or a light chain variable region comprising the three CDR sequences of SEQ ID NOs: 24, 25, and 26. In an embodiment, the anti-TIM-3 antibody agent comprises a heavy chain variable region comprising the three CDR sequences of SEQ ID NOs: 21, 22, and 23, and a light chain variable region comprising the three CDR sequences of SEQ ID NOs: 24, 25, and 26.

In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain having an amino acid sequence having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:1 or SEQ ID NO:7. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin light chain variable domain having an amino acid sequence having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:2 or SEQ ID NO:8. In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain having an amino acid sequence comprising SEQ ID NO:1 or SEQ ID NO:7, and/or an immunoglobulin light chain variable domain having an amino acid sequence comprising SEQ ID NO:2 or SEQ ID NO:8. In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain having an amino acid sequence comprising SEQ ID NO:1 or SEQ ID NO:7, and an immunoglobulin light chain variable domain having an amino acid sequence comprising SEQ ID NO:2 or SEQ ID NO:8.

In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain polypeptide comprising an amino acid sequence having about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:3. In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin light chain polypeptide comprising an amino acid sequence having about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:4. In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain having an amino acid sequence comprising SEQ ID NO:3, and/or an immunoglobulin light chain having an amino acid sequence comprising SEQ ID NO:4. In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain having an amino acid sequence comprising SEQ ID NO:3, and an immunoglobulin light chain having an amino acid sequence comprising SEQ ID NO:4.

In some embodiments, the disclosure provides a method of treating a disorder in a subject responsive to T cell immunoglobulin and mucin protein 3 (TIM-3) inhibition, comprising administering a therapeutically effective dose of an agent capable of inhibiting TIM-3 signaling. In embodiments, the therapeutically effective dose is about 1, 3, or 10 mg/kg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 100-1500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about a 100 mg flat dose; about a 200 mg flat dose; about a 300 mg flat dose; about a 400 mg flat dose; about a 500 mg flat dose; about a 600 mg flat dose; about a 700 mg flat dose; about a 800 mg flat dose; about a 900 mg flat dose; about a 1000 mg flat dose; about a 1100 mg flat dose; about a 1200 mg flat dose; about a 1300 mg flat dose; about a 1400 mg flat dose; or about a 1500 mg flat dose of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 1 mg/kg. In embodiments, the therapeutically effective dose is about 3 mg/kg. In embodiments, the therapeutically effective dose is about 10 mg/kg. In embodiments, the therapeutically effective dose is about a 100 mg flat dose of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about a 300 mg flat dose of the TIM-3 inhibitor. In an embodiment, the therapeutically effective dose is a flat dose of about 1200 mg of the TIM-3 inhibitor. In an embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody drug described herein.

In some embodiments, the disclosure provides a method of increasing T cell activation or T cell effector function in a subject responsive to T cell immunoglobulin and mucin protein 3 (TIM-3) inhibition, comprising administering a therapeutically effective dose of an agent capable of inhibiting TIM-3 signaling. In embodiments, the therapeutically effective dose is about 1, 3, or 10 mg/kg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 100-1500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about a 100 mg flat dose; about a 200 mg flat dose; about a 300 mg flat dose; about a 400 mg flat dose; about a 500 mg flat dose; about a 600 mg flat dose; about a 700 mg flat dose; about a 800 mg flat dose; about a 900 mg flat dose; about a 1000 mg flat dose; about a 1100 mg flat dose; about a 1200 mg flat dose; about a 1300 mg flat dose; about a 1400 mg flat dose; or about a 1500 mg flat dose of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 1 mg/kg. In embodiments, the therapeutically effective dose is about 3 mg/kg. In embodiments, the therapeutically effective dose is about 10 mg/kg. In embodiments, the therapeutically effective dose is about a 100 mg flat dose of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about a 300 mg flat dose of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a flat dose of about 500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a flat dose of about 900 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a flat dose of about 1200 mg of the TIM-3 inhibitor. In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent described herein.

In some embodiments, the disclosure provides a method of reducing tumors or inhibiting tumor cell growth in a subject responsive to T cell immunoglobulin and mucin protein 3 (TIM-3) inhibition, comprising administering a therapeutically effective dose of an agent capable of inhibiting TIM-3 signaling. In embodiments, the therapeutically effective dose is about 1, 3, or 10 mg/kg of a TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 100-1500 mg of a TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about a 100 mg flat dose; about a 200 mg flat dose; about a 300 mg flat dose; about a 400 mg flat dose; about a 500 mg flat dose; about a 600 mg flat dose; about a 700 mg flat dose; about a 800 mg flat dose; about a 900 mg flat dose; about a 1000 mg flat dose; about a 1100 mg flat dose; about a 1200 mg flat dose; about a 1300 mg flat dose; about a 1400 mg flat dose; or about a 1500 mg flat dose of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 1 mg/kg. In embodiments, the therapeutically effective dose is about 3 mg/kg. In embodiments, the therapeutically effective dose is about 10 mg/kg. In embodiments, the therapeutically effective dose is about a 100 mg flat dose of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about a 300 mg flat dose of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a flat dose of about 500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a flat dose of about 900 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a flat dose of about 1200 mg of the TIM-3 inhibitor. In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent described herein.

In some embodiments, the disclosure provides a method of inducing an immune response in a subject responsive to T cell immunoglobulin and mucin protein 3 (TIM-3) inhibition, comprising administering a therapeutically effective dose of an agent capable of inhibiting TIM-3 signaling. In embodiments, the therapeutically effective dose is about 1, 3, or 10 mg/kg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 100-1500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about a 100 mg flat dose; about a 200 mg flat dose; about a 300 mg flat dose; about a 400 mg flat dose; about a 500 mg flat dose; about a 600 mg flat dose; about a 700 mg flat dose; about a 800 mg flat dose; about a 900 mg flat dose; about a 1000 mg flat dose; about a 1100 mg flat dose; about a 1200 mg flat dose; about a 1300 mg flat dose; about a 1400 mg flat dose; or about a 1500 mg flat dose of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 1 mg/kg. In embodiments, the therapeutically effective dose is about 3 mg/kg. In embodiments, the therapeutically effective dose is about 10 mg/kg. In embodiments, the therapeutically effective dose is about a 100 mg flat dose of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about a 300 mg flat dose of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a flat dose of about 500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a flat dose of about 900 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a flat dose of about 1200 mg of the TIM-3 inhibitor. In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent described herein.

The present disclosure provides, in some embodiments, a method of enhancing an immune response or increasing immune cell activity in a subject responsive to T cell immunoglobulin and mucin protein 3 (TIM-3) inhibition, comprising administering a therapeutically effective dose of an agent capable of inhibiting TIM-3 signaling. In some embodiments, the immune response is a humoral or cell-mediated immune response. In some embodiments, the immune response is a CD4 T cell response or a CD8 T cell response. In some embodiments, the immune response is a B cell response. In embodiments, the therapeutically effective dose is about 1, 3, or 10 mg/kg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 100-1500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about a 100 mg flat dose; about a 200 mg flat dose; about a 300 mg flat dose; about a 400 mg flat dose; about a 500 mg flat dose; about a 600 mg flat dose; about a 700 mg flat dose; about a 800 mg flat dose; about a 900 mg flat dose; about a 1000 mg flat dose; about a 1100 mg flat dose; about a 1200 mg flat dose; about a 1300 mg flat dose; about a 1400 mg flat dose; or about a 1500 mg flat dose of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 1 mg/kg. In embodiments, the therapeutically effective dose is about 3 mg/kg. In embodiments, the therapeutically effective dose is about 10 mg/kg. In embodiments, the therapeutically effective dose is about a 100 mg flat dose of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about a 300 mg flat dose of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a flat dose of about 500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a flat dose of about 900 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a flat dose of about 1200 mg of the TIM-3 inhibitor. In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent described herein.

The present disclosure provides, in some embodiments, a method of treating cancer comprising administering to a patient in need of treatment a therapeutically effective dose of anti-T cell immunoglobulin and mucin domain-3 (TIM-3). In embodiments, the therapeutically effective dose is about 1, 3, or 10 mg/kg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 100-1500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about a 100 mg flat dose; about a 200 mg flat dose; about a 300 mg flat dose; about a 400 mg flat dose; about a 500 mg flat dose; about a 600 mg flat dose; about a 700 mg flat dose; about a 800 mg flat dose; about a 900 mg flat dose; about a 1000 mg flat dose; about a 1100 mg flat dose; about a 1200 mg flat dose; about a 1300 mg flat dose; about a 1400 mg flat dose; or about a 1500 mg flat dose of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about 1 mg/kg. In embodiments, the therapeutically effective dose is about 3 mg/kg. In embodiments, the therapeutically effective dose is about 10 mg/kg. In embodiments, the therapeutically effective dose is about a 100 mg flat dose of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is about a 300 mg flat dose of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a flat dose of about 500 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a flat dose of about 900 mg of the TIM-3 inhibitor. In embodiments, the therapeutically effective dose is a flat dose of about 1200 mg of the TIM-3 inhibitor. In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent described herein.

The present disclosure provides, in some embodiments, a method of treating cancer, comprising administering to a patient in need of treatment a therapeutically effective dose of an anti-T cell immunoglobulin and mucin domain-3 (TIM-3) antibody at a dosing interval for a period sufficient to achieve clinical benefit. In embodiments, the anti-TIM-3 antibody comprises a heavy chain comprising three CDRs having the sequence of SEQ ID NO:21, 22, or 23; and/or a light chain comprising three CDRs having the sequence of SEQ ID NO:24, 25, or 26. In embodiments, the anti-TIM-3 antibody comprises an immunoglobulin heavy chain variable domain comprising SEQ ID NO:1 or SEQ ID NO:7, and an immunoglobulin light chain variable domain comprising SEQ ID NO:2 or SEQ ID NO:8. In embodiments, the anti-TIM-3 antibody comprises a heavy chain polypeptide comprising SEQ ID NO:3, and a light chain polypeptide comprising SEQ ID NO:4. In embodiments, the therapeutically effective dose is about 1, 3, or 10 mg/kg of the anti-TIM-3 antibody. In embodiments, about 100-1500 mg of the anti-TIM-3 antibody. In embodiments, the therapeutically effective dose is about 100 mg flat dose; about 200 mg flat dose; about 300 mg flat dose; about 400 mg flat dose; about 500 mg flat dose; about 600 mg flat dose; about 700 mg flat dose; about 800 mg flat dose; about 900 mg flat dose; about 1000 mg flat dose; about 1100 mg flat dose; about 1200 mg flat dose; about 1300 mg flat dose; about 1400 mg flat dose; or about 1500 mg flat dose of anti-TIM-3 antibody. In embodiments, the therapeutically effective dose is about 1 mg/kg of anti-TIM-3 antibody. In embodiments, the therapeutically effective dose is about 3 mg/kg of anti-TIM-3 antibody. In embodiments, the therapeutically effective dose is about 10 mg/kg of anti-TIM-3 antibody. In an embodiment, the therapeutically effective dose is a flat dose of about 100 mg of an anti-TIM-3 antibody. In an embodiment, the therapeutically effective dose is a flat dose of about 300 mg of an anti-TIM-3 antibody. In an embodiment, the therapeutically effective dose is a flat dose of about 500 mg of a TIM-3 inhibitor. In an embodiment, the therapeutically effective dose is a flat dose of about 900 mg of a TIM-3 inhibitor. In an embodiment, the therapeutically effective dose is a flat dose of about 1200 mg of an anti-TIM-3 antibody.

In any of the methods described herein, the therapeutically effective dose is about 1 mg/kg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 3 mg/kg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 5 mg/kg of the TIM-3 inhibitor. In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent described herein.

In any of the methods described herein, the therapeutically effective dose is about 100 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 200 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 300 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 400 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 500 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 600 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 700 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 800 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 900 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 1000 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 1100 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 1200 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 1300 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 1400 mg of the TIM-3 inhibitor. In any of the methods described herein, the therapeutically effective dose is about 1500 mg of the TIM-3 inhibitor. In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent described herein.

In embodiments, the TIM-3 inhibitor is administered at a dosing interval (or treatment cycle) of once per week (Q1W), once per two weeks (Q2W), once per three weeks (Q3W), once per four weeks (Q4W), once per five weeks (Q5W), or once per six weeks (Q6W). In embodiments, the TIM-3 inhibitor is administered for a period of at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 weeks, or more. In embodiments, the TIM-3 inhibitor is administered at a dosing interval (or treatment cycle) of once per week (Q1W). In embodiments, the TIM-3 inhibitor is administered at a dosing interval (or treatment cycle) of once per two weeks (Q2W). In an embodiment, the TIM-3 inhibitor is administered at a dosing interval (or treatment cycle) of once every three weeks (Q3W). In an embodiment, the TIM-3 inhibitor is administered at a dosing interval (or treatment cycle) of once every four weeks (Q4W). In an embodiment, the TIM-3 inhibitor is administered at a dosing interval (or treatment cycle) of once every five weeks (Q5W). In an embodiment, the TIM-3 inhibitor is administered at a dosing interval (or treatment cycle) of once every six weeks (Q6W).

In embodiments, a therapeutically effective dose of a TIM-3 inhibitor (e.g., about 100 mg, 300 mg, 500 mg, or 900 mg) is administered at a three-week dosing interval (or treatment cycle). In embodiments, a therapeutically effective dose of about 100 mg is administered at a three-week dosing interval (or treatment cycle). In embodiments, a therapeutically effective dose of about 300 mg is administered at a three-week dosing interval (or treatment cycle). In embodiments, a therapeutically effective dose of about 500 mg is administered at a three-week dosing interval (or treatment cycle). In embodiments, a therapeutically effective dose of about 900 mg is administered at a three-week dosing interval (or treatment cycle).

In embodiments, the TIM-3 inhibitor is administered on the first day of a treatment cycle or within 1, 2, or 3 days of the first day of a treatment cycle. In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent described herein.

In embodiments, the TIM-3 inhibitor described herein is administered according to a dosing regimen demonstrated to achieve clinical benefit in some patients (e.g., according to a regimen determined by a physician, including dosing modifications). In embodiments, the TIM-3 inhibitor described herein is administered until treatment is discontinued, e.g., due to disease progression or adverse reactions, or by physician decision. In embodiments, the clinical benefit is stable disease ("SD"), partial response ("PR"), and/or complete response ("CR"). In embodiments, the clinical benefit is stable disease ("SD"). In embodiments, the clinical benefit is partial response ("PR"). In embodiments, the clinical benefit is complete response ("CR"). In embodiments, PR or CR is determined according to Response Evaluation Criteria in Solid Tumors (RECIST). In embodiments, the TIM-3 inhibitor is administered for a longer period of time to maintain the clinical benefit. In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody agent described herein.

In embodiments, the TIM-3 inhibitor is administered to the subject periodically at a dose of about 100 mg, about 300 mg, or about 1200 mg. In embodiments, the TIM-3 inhibitor is administered to the subject periodically at a dose of about 100 mg (e.g., once every three weeks (Q3W), and/or for 2, 3, 4, 5, 6 or more cycles). In embodiments, the TIM-3 inhibitor is administered to the subject periodically at a dose of about 300 mg (e.g., once every three weeks (Q3W), and/or for 2, 3, 4, 5, 6 or more cycles). In embodiments, the TIM-3 inhibitor is administered to the subject periodically at a dose of about 1200 mg (e.g., once every three weeks (Q3W), and/or for 2, 3, 4, 5, 6 or more cycles). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody drug described herein.

In embodiments, the subject has been or will be administered an additional therapeutic agent such that the subject receives a TIM-3 inhibitor (e.g., any anti-TIM-3 antibody agent described herein) and an additional therapeutic agent (e.g., one, two, three, four, or more additional therapeutic agents).

In embodiments, the subject has been or will be administered an immune checkpoint inhibitor, such that the subject receives a TIM-3 inhibitor (e.g., any anti-TIM-3 antibody agent described herein) and an immune checkpoint inhibitor. That is, the subject may be administered a TIM-3 inhibitor in combination with at least one immune checkpoint inhibitor.

In embodiments, the checkpoint inhibitor is an agent capable of inhibiting any of the following: PD-1 (e.g., inhibition via anti-PD-1, anti-PD-L1, or anti-PD-L2 therapy), CTLA-4, TIM-3, TIGIT, LAG (e.g., LAG-3), CEACAM (e.g., CEACAM-1, -3, and/or -5), VISTA, BTLA, LAIR1, CD16 0, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GALS, adenosine, TGFR (e.g., TGFR beta), B7-H1, B7-H4 (VTCN1), OX-40, CD137, CD40, IDO, or CSF-1R. In embodiments, the checkpoint inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the checkpoint inhibitor is an antibody, an antibody conjugate, or an antigen-binding fragment thereof.

In embodiments, the immune checkpoint inhibitor is an agent that inhibits programmed cell death protein 1 (PD-1) signaling, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), lymphocyte activation gene 3 (LAG-3), T-cell immunoglobulin and ITIM domain (TIGIT), indoleamine 2,3-dioxygenase (IDO), or colony-stimulating factor 1 receptor (CSF1R).

In embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor. In embodiments, the PD-1 inhibitor is a PD-1 binding agent (e.g., an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In embodiments, the PD-1 binding agent is nivolumab, pembrolizumab, TSR-042, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283, MGA012, BI-754091, IBI-308, camrelizumab (HR-301210), B CD-100, JS-001, CX-072, AMP-514/MEDI-0680, AGEN-2034, CS1001, TSR-042, Sym-021, PF-06801591, LZM009, KN-035, AB122, genolimuzumab (CBT-501), AK104, or GLS-010, or a derivative thereof. In embodiments, the PD-1 inhibitor is a PD-L1 or PD-L2 binding agent (e.g., an antibody, antibody conjugate, or antigen-binding fragment thereof). In embodiments, the PD-1 binding agent is a PD-L1 or PD-L2 binding agent and is durvalumab, atezolizumab, avelumab, BGB-A333, SHR-1316, FAZ-053, CK-301, or PD-L1 miramolecule, or derivatives thereof. In embodiments, the PD-1 inhibitor (e.g., TSR-042) is administered to the subject periodically at a dose of about 500 mg or 1000 mg. In embodiments, the PD-1 inhibitor (e.g., TSR-042) is administered to the subject periodically at a dose of about 500 mg or 1000 mg. In embodiments, the PD-1 inhibitor (e.g., TSR-042) is administered to the subject periodically at a dose of about 500 mg. In embodiments, the PD-1 inhibitor (e.g., TSR-042) is administered to the subject once every three weeks. In embodiments, the PD-1 inhibitor (e.g., TSR-042) is administered for 2, 3, 4, 5, 6 or more cycles. In embodiments, the PD-1 inhibitor (e.g., TSR-042) is administered for 4 cycles. In embodiments, the PD-1 inhibitor (e.g., TSR-042) is administered to the subject periodically at a dose of about 1000 mg. In embodiments, the PD-1 inhibitor (e.g., TSR-042) is administered to the subject once every 6 weeks. In embodiments, the PD-1 inhibitor (e.g., TSR-042) is administered at a first dose of about 500 mg once every 3 weeks for 4 cycles, then at a second dose of about 1000 mg once every 6 weeks (e.g., until treatment is discontinued).

In embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor (e.g., an antibody, antibody conjugate, or antigen-binding fragment thereof). In embodiments, the CTLA-4 inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the CTLA-4 inhibitor is a small molecule. In embodiments, the CTLA-4 inhibitor is a CTLA-4 binding agent. In embodiments, the CTLA-4 inhibitor is an antibody, antibody conjugate, or antigen-binding fragment thereof. In embodiments, the CTLA-4 inhibitor is ipilimumab (Yervoy), AGEN1884, or tremelimumab.

In embodiments, the immune checkpoint inhibitor is a LAG-3 inhibitor (e.g., an antibody, antibody conjugate, or antigen-binding fragment thereof). In embodiments, the LAG-3 inhibitor is a small molecule, nucleic acid, polypeptide (e.g., an antibody), carbohydrate, lipid, metal, or toxin. In embodiments, the LAG-3 inhibitor is a small molecule. In embodiments, the LAG-3 inhibitor is a LAG-3 binding agent. In embodiments, the LAG-3 inhibitor is an antibody, antibody conjugate, or antigen-binding fragment thereof. In embodiments, the LAG-3 inhibitor is IMP321, BMS-986016, GSK2831781, Novartis
LAG525, or a LAG-3 inhibitor as described in WO2016/126858, WO2017/019894, or WO2015/138920, each of which is incorporated by reference in its entirety.

In embodiments, the immune checkpoint inhibitor is a TIGIT inhibitor (e.g., an antibody, antibody conjugate, or antigen-binding fragment thereof). In embodiments, the TIGIT inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the TIGIT inhibitor is a small molecule. In embodiments, the TIGIT inhibitor is a TIGIT binding agent. In embodiments, the TIGIT inhibitor is an antibody, antibody conjugate, or antigen-binding fragment thereof. In embodiments, the TIGIT inhibitor is MTIG7192A, BMS-986207, or OMP-31M32.

In embodiments, the immune checkpoint inhibitor is an IDO inhibitor. In embodiments, the IDO inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the IDO inhibitor is a small molecule. In embodiments, the IDO inhibitor is an IDO binding agent. In embodiments, the IDO inhibitor is an antibody, an antibody conjugate, or an antigen-binding fragment thereof.

In embodiments, the immune checkpoint inhibitor is a CSF1R inhibitor. In embodiments, the CSF1R inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the CSF1R inhibitor is a small molecule. In embodiments, the CSF1R inhibitor is a CSF1R binding agent. In embodiments, the CSF1R inhibitor is an antibody, an antibody conjugate, or an antigen-binding fragment thereof.

In embodiments, the method includes administering a TIM-3 inhibitor (e.g., any anti-TIM-3 antibody agent described herein) with at least two of the immune checkpoint inhibitors. In embodiments, the method includes administering a third checkpoint inhibitor. In embodiments, the method includes administering a TIM-3 inhibitor with a PD-1 inhibitor and a LAG-3 inhibitor, such that the subject receives all three. In embodiments, the method includes administering a TIM-3 inhibitor with a PD-1 inhibitor, a LAG-3 inhibitor, and a CTLA-4 inhibitor, such that the subject receives all four.

In an embodiment, the subject has been or will be administered an agent that inhibits poly(ADP-ribose) polymerase (PARP), such that the subject is treated with a TIM-3 inhibitor and a PARP inhibitor.

In embodiments, the PARP inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the PARP inhibitor is selected from the group consisting of: ABT-767, AZD 2461, BGB-290, BGP 15, CEP 8983, CEP 9722, DR 2313, E7016, E7449, fluzoparib, IMP 4297, INO1001, JPI 289, JPI 547, monoclonal antibody B3-LysPE40 conjugate, MP 124, niraparib, NU 1025, NU 1064, NU 1076, NU1085, olaparib, ONO2231, PD 128763, R 503, R554, rucaparib, SBP 101, SC 101914, simmiparib, talazoparib, veliparib, WW 46, 2-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-ol, and salts or derivatives thereof. In embodiments, the PARP inhibitor is niraparib, olaparib, rucaparib, talazoparib, or veliparib. In embodiments, the PARP inhibitor is niraparib (e.g., niraparib free base, niraparib tosylate, or niraparib tosylate monohydrate, or any combination thereof).

In an embodiment, the subject has been or will be administered one or more immune checkpoint inhibitors (e.g., a PD-1 inhibitor and/or a LAG-3 inhibitor), such that the subject is treated with a TIM-3 inhibitor, a PARP inhibitor (e.g., niraparib), and one or more immune checkpoint inhibitors. In an embodiment, the subject is administered a TIM-3 inhibitor, a PD-1 inhibitor (e.g., TSR-042), and a PARP inhibitor (e.g., niraparib). In an embodiment, the subject is administered a TIM-3 inhibitor, a PD-1 inhibitor (e.g., TSR-042), a LAG-3 inhibitor, and a PARP inhibitor (e.g., niraparib).

In an embodiment, the patient has a disorder that is a T cell dysfunction disorder.

In an embodiment, the patient has a disorder that is cancer.

In an embodiment, the cancer is associated with high tumor mutation burden (TMB).

In an embodiment, the cancer is microsatellite stable (MSS).

In an embodiment, the cancer is characterized by microsatellite instability.

In an embodiment, the cancer has microsatellite instability high status (MSI-H).

In an embodiment, the cancer has a microsatellite instability low status (MSI-L).

In an embodiment, the cancer is associated with high TMB and MSI-H.

In an embodiment, the cancer is associated with high TMB and MSI-L or MSS. In an embodiment, the cancer is associated with high TMB and MSI-L. In an embodiment, the cancer is associated with high TMB and MSS.

In an embodiment, the cancer has a defective DNA mismatch repair system.

In an embodiment, the cancer has a defect in a DNA mismatch repair gene.

In an embodiment, the cancer is a hypermutable cancer.

In an embodiment, the cancer has a homology directed repair deficiency/homology directed repair deficiency ("HRD").

In an embodiment, the cancer comprises a mutation in polymerase delta (POLD).

In an embodiment, the cancer comprises a mutation in polymerase epsilon (POLE).

In embodiments, the cancer is an adenocarcinoma, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, testicular cancer, primary peritoneal cancer, colon cancer, colorectal cancer, gastric cancer, small intestine cancer, squamous cell carcinoma of the anogenital tract (e.g., squamous cell carcinoma of the anus, penis, cervix, vagina, or vulva), soft tissue sarcoma (e.g., leiomyosarcoma), melanoma, renal cell carcinoma, lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung, gastric cancer, bladder cancer, gallbladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, cancer, esophageal cancer, head and neck cancer, squamous cell carcinoma of the head and neck, prostate cancer, pancreatic cancer, mesothelioma, Merkel cell carcinoma, sarcoma, glioblastoma, blood cancer, multiple myeloma, B cell lymphoma, T cell lymphoma, Hodgkin lymphoma (HL)/primary mediastinal B cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, acute lymphocytic leukemia, non-Hodgkin lymphoma, neuroblastoma, central nervous system tumor, diffuse intrinsic pontine glioma (DIPG), Ewing's sarcoma, embryonal rhabdomyosarcoma, osteosarcoma, or Wilms' tumor. In embodiments, the cancer is MSS or MSI-L, is characterized by microsatellite instability, is MSI-H, has high TMB and is MSS or MSI-L, has high TMB and is MSI-H, has a defective DNA mismatch repair system, has defects in DNA mismatch repair genes, is a hypermutable cancer, is an HRD cancer, contains a mutation in polymerase delta (POLD), or contains a mutation in polymerase epsilon (POLE).

In embodiments, the cancer is endometrial cancer (e.g., MSI-H or MSS/MSI-L endometrial cancer). In embodiments, the cancer is MSI-H cancer with a mutation in POLE or POLD (e.g., MSI-H non-endometrial cancer with a mutation in POLE or POLD). In embodiments, the cancer is breast cancer (triple negative breast cancer (TNBC)). In embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer). In embodiments, the cancer is melanoma. In embodiments, the cancer is colorectal cancer. In embodiments, the cancer is squamous cell carcinoma of the anus, squamous cell carcinoma of the penis, squamous cell carcinoma of the cervix, squamous cell carcinoma of the vagina, or squamous cell carcinoma of the vulva.

In embodiments, the cancer has a homologous recombination repair deficiency/homologous repair deficiency ("HRD"). In embodiments, the cancer is acute myeloid leukemia. In embodiments, the cancer is acute lymphoblastic leukemia. In embodiments, the cancer is non-Hodgkin's lymphoma. In embodiments, the cancer is Hodgkin's lymphoma. In embodiments, the cancer is neuroblastoma. In embodiments, the cancer is a central nervous system tumor. In embodiments, the cancer is diffuse intrinsic pontine glioma (DIPG). In embodiments, the cancer is Ewing's sarcoma. In embodiments, the cancer is embryonal rhabdomyosarcoma. In embodiments, the cancer is osteosarcoma. In embodiments, the cancer is Wilms' tumor. In embodiments, the cancer is a soft tissue sarcoma (e.g., leiomyosarcoma).

In some embodiments, the patient has cancer, e.g., non-small cell lung cancer (NSCLC), hepatocellular carcinoma, renal cancer, melanoma, cervical cancer, colorectal cancer, squamous cell carcinoma of the anogenital region, head and neck cancer, triple-negative breast cancer, ovarian cancer, or endometrial cancer. In some embodiments, the patient has cancer with microsatellite instability. In some embodiments, microsatellite instability is considered frequent when it is significantly higher than the instability observed in control cells. In some embodiments, the patient has a solid tumor. In some embodiments, the patient has an advanced stage solid tumor. In some embodiments, the patient has an advanced stage solid tumor, e.g., non-small cell lung cancer (NSCLC), hepatocellular carcinoma, renal cancer, melanoma, cervical cancer, colorectal cancer, squamous cell carcinoma of the anogenital region, head and neck cancer, triple-negative breast cancer, ovarian cancer, or endometrial cancer. In some embodiments, the patient has an advanced stage solid tumor with microsatellite instability.

In some embodiments, the patient has a hematological cancer, such as diffuse large B-cell lymphoma ("DLBCL"), Hodgkin's lymphoma ("HL"), non-Hodgkin's lymphoma ("NHL"), follicular lymphoma ("FL"), acute myeloid leukemia ("AML"), acute lymphoblastic leukemia ("ALL"), or multiple myeloma ("MM"). In some embodiments, the patient has a hematological cancer with microsatellite instability.

In some embodiments, the patient has a cancer characterized by PD-1 and/or PD-L1 expression. In some embodiments, the cancer has high PD-1 and/or PD-L1 expression (e.g., by high PD-1 and/or high PD-L1 expression). In some embodiments, the cancer characterized by PD-1 and/or PD-L1 expression is head and neck cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), kidney cancer, bladder cancer, melanoma, Merkel cell carcinoma, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, breast cancer, prostate cancer, oral adenocarcinoma, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendix cancer, urothelial cell carcinoma, or squamous cell carcinoma (e.g., lung; anogenital region, including anus, penis, cervix, vagina, or vulva; or esophageal squamous cell carcinoma). In some certain embodiments, the cancer characterized by PD-1 and/or PD-L1 expression is anal cancer, fallopian tube cancer, ovarian cancer, or lung cancer.

In some embodiments, the patient has head and neck cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), kidney cancer, bladder cancer, melanoma, Merkel cell carcinoma, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, breast cancer, prostate cancer, oral adenocarcinoma, thymoma, adrenal cortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendix cancer, urothelial cell carcinoma, or squamous cell carcinoma.

In embodiments, the cancer is an advanced cancer. In embodiments, the cancer is a metastatic cancer. In embodiments, the cancer is an MSI-H cancer. In embodiments, the cancer is an MSS cancer. In embodiments, the cancer is a POLE mutated cancer. In embodiments, the cancer is a POLD mutated cancer. In embodiments, the cancer is a TMB high cancer. In embodiments, the cancer is associated with homologous recombination repair deficiency/homology repair deficiency ("HRD").

In embodiments, the cancer is a solid tumor. In embodiments, the solid tumor is advanced. In embodiments, the solid tumor is a metastatic solid tumor. In embodiments, the solid tumor is an MSI-H solid tumor. In embodiments, the solid tumor is an MSS solid tumor. In embodiments, the solid tumor is a POLE mutated solid tumor. In embodiments, the solid tumor is a POLD mutated solid tumor. In embodiments, the solid tumor is a TMB high solid tumor. In embodiments, the solid tumor is associated with homologous recombination repair deficiency/homology repair deficiency ("HRD").

In embodiments, the cancer is a non-endometrial cancer (e.g., a non-endometrial solid tumor). In embodiments, the non-endometrial cancer is an advanced cancer. In embodiments, the non-endometrial cancer is a metastatic cancer. In embodiments, the non-endometrial cancer is an MSI-H cancer. In embodiments, the non-endometrial cancer is an MSS cancer. In embodiments, the non-endometrial cancer is a POLE mutated cancer. In embodiments, the non-endometrial cancer is a solid tumor (e.g., an MSS solid tumor, an MSI-H solid tumor, a POLD mutated solid tumor, or a POLE mutated solid tumor). In embodiments, the non-endometrial cancer is a TMB high cancer. In embodiments, the non-endometrial cancer is associated with homologous recombination repair deficiency/homology repair deficiency ("HRD").

In embodiments, the cancer is endometrial cancer (e.g., a solid tumor). In embodiments, the endometrial cancer is an advanced cancer. In embodiments, the endometrial cancer is a metastatic cancer. In embodiments, the endometrial cancer is an MSI-H endometrial cancer. In embodiments, the endometrial cancer is an MSS endometrial cancer. In embodiments, the endometrial cancer is a POLE mutant endometrial cancer. In embodiments, the endometrial cancer is a POLD mutant endometrial cancer. In embodiments, the endometrial cancer is a TMB high endometrial cancer. In embodiments, the endometrial cancer is associated with homologous recombination repair deficiency/homology repair deficiency ("HRD").

In embodiments, the cancer is lung cancer (e.g., a solid tumor). In embodiments, the lung cancer is advanced lung cancer. In embodiments, the lung cancer is metastatic lung cancer. In embodiments, the lung cancer is squamous cell carcinoma of the lung. In embodiments, the lung cancer is small cell lung cancer (SCLC). In embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In embodiments, the lung cancer is ALK translocation lung cancer (e.g., lung cancer with a known ALK translocation). In embodiments, the lung cancer is EGFR mutated lung cancer (e.g., lung cancer with a known EGFR mutation). In embodiments, the lung cancer is MSI-H lung cancer. In embodiments, the lung cancer is MSS lung cancer. In embodiments, the lung cancer is POLE mutated lung cancer. In embodiments, the lung cancer is POLD mutated lung cancer. In embodiments, the lung cancer is TMB high lung cancer. In an embodiment, the lung cancer is associated with homology directed repair deficiency/homology directed repair deficiency ("HRD").

In embodiments, the cancer is colorectal (CRC) cancer (e.g., solid tumor). In embodiments, the colorectal cancer is advanced colorectal cancer. In embodiments, the colorectal cancer is metastatic colorectal cancer. In embodiments, the colorectal cancer is MSI-H colorectal cancer. In embodiments, the colorectal cancer is MSS colorectal cancer. In embodiments, the colorectal cancer is POLE mutated colorectal cancer. In embodiments, the colorectal cancer is POLD mutated colorectal cancer. In embodiments, the colorectal cancer is TMB high colorectal cancer. In embodiments, the colorectal cancer is associated with homologous recombination repair deficiency/homology repair deficiency ("HRD").

In embodiments, the cancer is melanoma. In embodiments, the melanoma is advanced melanoma. In embodiments, the melanoma is metastatic melanoma. In embodiments, the melanoma is MSI-H melanoma. In embodiments, the melanoma is MSS melanoma. In embodiments, the melanoma is POLE mutated melanoma. In embodiments, the melanoma is POLD mutated melanoma. In embodiments, the melanoma is TMB high melanoma. In embodiments, the melanoma is associated with homologous recombination repair deficiency/homology repair deficiency ("HRD").

In embodiments, the cancer is squamous cell carcinoma of the anogenital region (e.g., anus, penis, cervix, vagina, or vulva). In embodiments, the squamous cell carcinoma of the anogenital region (e.g., anus, penis, cervix, vagina, or vulva) is an advanced cancer. In embodiments, the squamous cell carcinoma of the anogenital region (e.g., anus, penis, cervix, vagina, or vulva) is a metastatic cancer. In embodiments, the squamous cell carcinoma of the anogenital region (e.g., anus, penis, cervix, vagina, or vulva) is MSI-H. In embodiments, the squamous cell carcinoma of the anogenital region (e.g., anus, penis, cervix, vagina, or vulva) is MSS. In embodiments, the lung cancer is a POLE-mutated cancer. In embodiments, squamous cell carcinoma of the anogenital region (e.g., anus, penis, cervix, vagina, or vulva) is associated with homologous recombination deficiency/homology repair deficiency ("HRD").

In embodiments, the cancer is ovarian cancer. In embodiments, the ovarian cancer is advanced ovarian cancer. In embodiments, the ovarian cancer is metastatic ovarian cancer. In embodiments, the ovarian cancer is MSI-H ovarian cancer. In embodiments, the ovarian cancer is MSS ovarian cancer. In embodiments, the ovarian cancer is POLE mutated ovarian cancer. In embodiments, the ovarian cancer is POLD mutated ovarian cancer. In embodiments, the ovarian cancer is TMB high ovarian cancer. In embodiments, the ovarian cancer is associated with homologous recombination repair deficiency/homologous repair deficiency ("HRD"). In embodiments, the ovarian cancer is serous cell ovarian cancer. In embodiments, the ovarian cancer is clear cell ovarian cancer.

In embodiments, the cancer is a fallopian cancer. In embodiments, the fallopian cancer is advanced fallopian cancer. In embodiments, the fallopian cancer is metastatic fallopian cancer. In embodiments, the fallopian cancer is MSI-H fallopian cancer. In embodiments, the fallopian cancer is MSS fallopian cancer. In embodiments, the fallopian cancer is POLE mutated fallopian cancer. In embodiments, the fallopian cancer is POLD mutated fallopian cancer. In embodiments, the fallopian cancer is TMB high fallopian cancer. In embodiments, the fallopian cancer is associated with homologous recombination repair deficiency/homology repair deficiency ("HRD"). In embodiments, the fallopian cancer is serous cell fallopian cancer. In embodiments, the fallopian cancer is clear cell fallopian cancer.

In embodiments, the cancer is a primary peritoneal cancer. In embodiments, the primary peritoneal cancer is an advanced primary peritoneal cancer. In embodiments, the primary peritoneal cancer is a metastatic primary peritoneal cancer. In embodiments, the primary peritoneal cancer is an MSI-H primary peritoneal cancer. In embodiments, the primary peritoneal cancer is an MSS primary peritoneal cancer. In embodiments, the primary peritoneal cancer is a POLE-mutated primary peritoneal cancer. In embodiments, the primary peritoneal cancer is a POLD-mutated primary peritoneal cancer. In embodiments, the primary peritoneal cancer is a TMB-high primary peritoneal cancer. In embodiments, the primary peritoneal cancer is associated with homologous recombination repair deficiency/homology repair deficiency ("HRD"). In embodiments, the primary peritoneal cancer is a serous cell primary peritoneal cancer. In embodiments, the primary peritoneal cancer is a clear cell primary peritoneal cancer.

In embodiments, the cancer is acute lymphoblastic leukemia ("ALL"). In embodiments, the acute lymphoblastic leukemia is advanced acute lymphoblastic leukemia. In embodiments, the acute lymphoblastic leukemia is metastatic acute lymphoblastic leukemia. In embodiments, the acute lymphoblastic leukemia is MSI-H acute lymphoblastic leukemia. In embodiments, the acute lymphoblastic leukemia is MSS acute lymphoblastic leukemia. In embodiments, the acute lymphoblastic leukemia is POLE-mutated acute lymphoblastic leukemia. In embodiments, the acute lymphoblastic leukemia is POLD-mutated acute lymphoblastic leukemia. In embodiments, the acute lymphoblastic leukemia is associated with homologous recombination repair deficiency/homology repair deficiency ("HRD").

In embodiments, the cancer is acute myeloid leukemia ("AML"). In embodiments, the acute myeloid leukemia is advanced acute myeloid leukemia. In embodiments, the acute myeloid leukemia is metastatic acute myeloid leukemia. In embodiments, the acute myeloid leukemia is MSI-H acute myeloid leukemia. In embodiments, the acute myeloid leukemia is MSS acute myeloid leukemia. In embodiments, the acute myeloid leukemia is POLE mutated acute myeloid leukemia. In embodiments, the acute myeloid leukemia is POLD mutated acute myeloid leukemia. In embodiments, the acute myeloid leukemia is associated with homologous recombination repair deficiency/homology repair deficiency ("HRD").

In an embodiment, the cancer is non-Hodgkin's lymphoma (NHL). In an embodiment, the non-Hodgkin's lymphoma is advanced non-Hodgkin's lymphoma. In an embodiment, the non-Hodgkin's lymphoma is metastatic non-Hodgkin's lymphoma. In an embodiment, the non-Hodgkin's lymphoma is MSI-H non-Hodgkin's lymphoma. In an embodiment, the non-Hodgkin's lymphoma is MSS non-Hodgkin's lymphoma. In an embodiment, the non-Hodgkin's lymphoma is POLE mutated non-Hodgkin's lymphoma. In an embodiment, the non-Hodgkin's lymphoma is POLD mutated non-Hodgkin's lymphoma. In an embodiment, the non-Hodgkin's lymphoma is associated with homologous recombination repair deficiency/homology repair deficiency ("HRD").

In an embodiment, the cancer is Hodgkin lymphoma (HL). In an embodiment, the Hodgkin lymphoma is advanced Hodgkin lymphoma. In an embodiment, the Hodgkin lymphoma is metastatic Hodgkin lymphoma. In an embodiment, the Hodgkin lymphoma is MSI-H Hodgkin lymphoma. In an embodiment, the Hodgkin lymphoma is MSS Hodgkin lymphoma. In an embodiment, the Hodgkin lymphoma is POLE mutated Hodgkin lymphoma. In an embodiment, the Hodgkin lymphoma is POLD mutated Hodgkin lymphoma. In an embodiment, the Hodgkin lymphoma is associated with homologous recombination repair deficiency/homology repair deficiency ("HRD").

In an embodiment, the cancer is neuroblastoma (NB). In an embodiment, the neuroblastoma is advanced neuroblastoma. In an embodiment, the neuroblastoma is metastatic neuroblastoma. In an embodiment, the neuroblastoma is MSI-H neuroblastoma. In an embodiment, the neuroblastoma is MSS neuroblastoma. In an embodiment, the neuroblastoma is POLE mutant neuroblastoma. In an embodiment, the neuroblastoma is POLD mutant neuroblastoma. In an embodiment, the neuroblastoma is TMB high neuroblastoma. In an embodiment, the neuroblastoma is associated with homologous recombination repair deficiency/homology repair deficiency ("HRD").

In embodiments, the cancer is a central nervous system tumor. In embodiments, the central nervous system tumor is advanced. In embodiments, the central nervous system tumor is a metastatic central nervous system tumor. In embodiments, the central nervous system tumor is an MSI-H central nervous system tumor. In embodiments, the central nervous system tumor is an MSS central nervous system tumor. In embodiments, the central nervous system tumor is a POLE mutated central nervous system tumor. In embodiments, the central nervous system tumor is a POLD mutated central nervous system tumor. In embodiments, the central nervous system tumor is a TMB high central nervous system tumor. In embodiments, the central nervous system tumor is associated with homologous recombination repair deficiency/homology repair deficiency ("HRD").

In an embodiment, the cancer is diffuse intrinsic pontine glioma (DIPG). In an embodiment, the DIPG is advanced DIPG. In an embodiment, the DIPG is metastatic DIPG. In an embodiment, the DIPG is MSI-H DIPG. In an embodiment, the DIPG is MSS DIPG. In an embodiment, the DIPG is POLE mutated DIPG. In an embodiment, the DIPG is POLD mutated DIPG. In an embodiment, the DIPG is TMB high DIPG. In an embodiment, the DIPG is associated with homology directed repair deficiency/homology repair deficiency ("HRD").

In embodiments, the cancer is Ewing's sarcoma. In embodiments, the Ewing's sarcoma is advanced Ewing's sarcoma. In embodiments, the Ewing's sarcoma is metastatic Ewing's sarcoma. In embodiments, the Ewing's sarcoma is MSI-H Ewing's sarcoma. In embodiments, the Ewing's sarcoma is MSS Ewing's sarcoma. In embodiments, the Ewing's sarcoma is POLE-mutated Ewing's sarcoma. In embodiments, the Ewing's sarcoma is POLD-mutated Ewing's sarcoma. In embodiments, the Ewing's sarcoma is TMB-high Ewing's sarcoma. In embodiments, the Ewing's sarcoma is associated with homologous recombination repair deficiency/homology repair deficiency ("HRD").

In an embodiment, the cancer is embryonal rhabdomyosarcoma (ERS). In an embodiment, the embryonal rhabdomyosarcoma is advanced embryonal rhabdomyosarcoma. In an embodiment, the embryonal rhabdomyosarcoma is metastatic embryonal rhabdomyosarcoma. In an embodiment, the embryonal rhabdomyosarcoma is MSI-H embryonal rhabdomyosarcoma. In an embodiment, the embryonal rhabdomyosarcoma is MSS embryonal rhabdomyosarcoma. In an embodiment, the embryonal rhabdomyosarcoma is POLE mutated embryonal rhabdomyosarcoma. In an embodiment, the embryonal rhabdomyosarcoma is POLD mutated embryonal rhabdomyosarcoma. In an embodiment, the embryonal rhabdomyosarcoma is TMB high embryonal rhabdomyosarcoma. In an embodiment, the embryonal rhabdomyosarcoma is associated with homologous recombination repair deficiency/homology repair deficiency ("HRD").

In an embodiment, the cancer is osteosarcoma (OS). In an embodiment, the osteosarcoma is advanced osteosarcoma. In an embodiment, the osteosarcoma is metastatic osteosarcoma. In an embodiment, the osteosarcoma is MSI-H osteosarcoma. In an embodiment, the osteosarcoma is MSS osteosarcoma. In an embodiment, the osteosarcoma is POLE-mutated osteosarcoma. In an embodiment, the osteosarcoma is POLD-mutated osteosarcoma. In an embodiment, the osteosarcoma is TMB-high osteosarcoma. In an embodiment, the osteosarcoma is associated with homologous recombination repair deficiency/homology repair deficiency ("HRD").

In embodiments, the cancer is a soft tissue sarcoma. In embodiments, the soft tissue sarcoma is an advanced soft tissue sarcoma. In embodiments, the soft tissue sarcoma is a metastatic soft tissue sarcoma. In embodiments, the soft tissue sarcoma is an MSI-H soft tissue sarcoma. In embodiments, the soft tissue sarcoma is an MSS soft tissue sarcoma. In embodiments, the soft tissue sarcoma is a POLE-mutated soft tissue sarcoma. In embodiments, the soft tissue sarcoma is a POLD-mutated soft tissue sarcoma. In embodiments, the soft tissue sarcoma is a TMB-high soft tissue sarcoma. In embodiments, the soft tissue sarcoma is associated with homologous recombination repair deficiency/homology repair deficiency ("HRD"). In embodiments, the soft tissue sarcoma is a leiomyosarcoma.

In embodiments, the cancer is Wilms tumor. In embodiments, the Wilms tumor is advanced Wilms tumor. In embodiments, the Wilms tumor is metastatic Wilms tumor. In embodiments, the Wilms tumor is MSI-H Wilms tumor. In embodiments, the Wilms tumor is MSS Wilms tumor. In embodiments, the Wilms tumor is POLE mutated Wilms tumor. In embodiments, the Wilms tumor is POLD mutated Wilms tumor. In embodiments, the Wilms tumor is TMB high Wilms tumor. In embodiments, the Wilms tumor is associated with homologous recombination repair deficiency/homology repair deficiency ("HRD").

In embodiments, the subject has previously been treated with one or more different cancer treatment modalities (e.g., one or more of surgery, radiation therapy, chemotherapy, or immunotherapy).

In embodiments, the subject has been previously treated with one different cancer treatment modality (e.g., one or more of surgery, radiation therapy, chemotherapy, or immunotherapy). In embodiments, the subject has been previously treated with two or more different cancer treatment modalities (e.g., one or more of surgery, radiation therapy, chemotherapy, or immunotherapy). In embodiments, the subject has been previously treated with a cytotoxic therapy. In embodiments, the subject has been previously treated with chemotherapy. In embodiments, the subject has been previously treated with two different cancer treatment modalities (e.g., one or more of surgery, radiation therapy, chemotherapy, or immunotherapy). In embodiments, the subject has been previously treated with three different cancer treatment modalities (e.g., one or more of surgery, radiation therapy, chemotherapy, or immunotherapy).

In embodiments of the methods described herein, the methods further include administering one or more of surgery, radiation therapy, chemotherapy, immunotherapy, an anti-angiogenic agent, or an anti-inflammatory agent. In embodiments, the methods further include administering chemotherapy.

In some embodiments, at least some patients in the cancer patient population have been previously treated with chemotherapy (e.g., platinum-based chemotherapy). For example, patients who have undergone two lines of cancer treatment may be identified as 2L cancer patients (e.g., 2L NSCLC patients). In embodiments, the patients have undergone more than one line of cancer treatment (e.g., 2L+ cancer patients, e.g., 2L+ endometrial cancer patients). In embodiments, the patients have not been previously treated with anti-PD-1 therapy. In embodiments, the patients have undergone at least one line of cancer treatment (e.g., the patients have undergone at least one or at least two lines of cancer treatment). In embodiments, the patients have undergone at least one line of metastatic cancer treatment (e.g., the patients have undergone one or two lines of metastatic cancer treatment).

In an embodiment, the subject is resistant to treatment with an agent that inhibits PD-1.

In an embodiment, the subject is refractory to treatment with an agent that inhibits PD-1.

In embodiments, the methods described herein sensitize a subject to treatment with an agent that inhibits PD-1.

In an embodiment, the subject comprises exhausted immune cells (e.g., exhausted immune cells that are exhausted T cells).

In embodiments of the methods described herein, the subject is an animal (e.g., a mammal). In embodiments, the subject is a human. In embodiments, the subject is a non-human mammal (e.g., a mouse, a rat, a rabbit, or a non-human primate). Thus, the methods described herein may be useful in both human treatment and veterinary medicine.

In embodiments, the TIM-3 inhibitor is administered intravenously (e.g., by intravenous infusion).

The present disclosure provides, in some embodiments, a method of treating cancer in a patient in need of such treatment, comprising administering a composition that delivers an anti-TIM-3 antibody agent.

In some embodiments, the patient has not been previously treated with the cancer treatment modality.

In some embodiments, the patient has been previously treated with one or more different cancer treatment modalities. In some embodiments, the patient has been previously treated with one or more of radiation therapy, chemotherapy, or immunotherapy. In some embodiments, the patient has been previously treated with chemotherapy (e.g., platinum-based chemotherapy).

In some embodiments, the composition delivering the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is administered at a dose of 1, 3, or 10 mg/kg. In some embodiments, the composition delivering the anti-TIM-3 antibody drug is administered according to a regimen including a dose of 1, 3, or 10 mg/kg once every two weeks. In some embodiments, the composition delivering the anti-TIM-3 antibody drug is administered according to a regimen including a dose of 1, 3, or 10 mg/kg once every three weeks. In some embodiments, the composition delivering the anti-TIM-3 antibody drug is administered according to a regimen including a dose of 1, 3, or 10 mg/kg once every four weeks.

In some embodiments, the composition delivering the anti-TIM-3 antibody agent is a fixed dose in the range of about 100 mg to about 1500 mg (e.g., about 100 mg to 1500 mg). In some embodiments, the composition delivering the anti-TIM-3 antibody agent is a fixed dose in the range of about 100 mg to about 300 mg, about 300 mg to 1,000 mg, or about 1000 mg to about 1200 mg. In embodiments, the fixed dose is about 100 mg. In embodiments, the fixed dose is about 300 mg. In embodiments, the fixed dose is about 500 mg. In embodiments, the fixed dose is about 900 mg. In embodiments, the fixed dose is about 1200 mg. In some embodiments, the composition delivering the anti-TIM-3 antibody agent is administered according to a regimen including a fixed dose once every two weeks (Q2W). In some embodiments, the composition delivering the anti-TIM-3 antibody agent is administered according to a regimen including a fixed dose once every three weeks (Q3W). In some embodiments, the composition delivering the anti-TIM-3 antibody agent is administered according to a regimen comprising a fixed dose once every four weeks (Q4W). In embodiments, the anti-TIM-3 antibody is administered at a dosing interval of once per week (Q1W), once per two weeks (Q2W), once per three weeks (S3W), once per four weeks (Q4W), once per five weeks (Q5W), or once per six weeks (Q6W). In embodiments, the anti-TIM-3 antibody is administered for a period of at least 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 weeks. In embodiments, the dose is administered as a monotherapy (e.g., a therapeutically effective amount of 1200 mg of anti-TIM-3 antibody is administered Q2W or Q3W) or the dose is administered in combination with one or more other therapies. For example, 100 mg, 300 mg, 500 mg, or 900 mg (e.g., 100 mg or 300 mg) of an anti-TIM-3 antibody may be administered in combination with an anti-PD-1 antibody according to the regimen described herein (e.g., 500 mg of an anti-PD-1 antibody administered Q3W for four treatment cycles, followed by 1000 mg of an anti-PD-1 antibody administered Q6W until treatment is discontinued (e.g., due to disease progression)).

In some embodiments, the composition is administered intravenously. In some embodiments, the composition is administered by intravenous infusion.

In some embodiments, the clinical benefit is a complete response ("CR"), partial response ("PR"), or stable disease ("SD"). In some embodiments, the clinical benefit corresponds to at least a SD. In some embodiments, the clinical benefit corresponds to at least a PR. In some embodiments, the clinical benefit corresponds to a CR. In some embodiments, at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of patients achieve a clinical benefit. In some embodiments, at least 5% of patients achieve a clinical benefit. In some embodiments, at least 5% of patients achieve a SD. In some embodiments, at least 5% of patients achieve at least a PR. In some embodiments, at least 5% of patients achieve a CR. In some embodiments, at least 20% of patients achieve a clinical benefit. In some embodiments, at least 20% of patients achieve SD.

In some embodiments, clinical benefit (e.g., SD, PR, and/or CR) is determined according to Response Evaluation Criteria in Solid Tumors (RECIST). In some embodiments, clinical benefit (e.g., SD, PR, and/or CR) is determined according to RECIST guidelines. In some embodiments, clinical benefit (e.g., SD, PR, and/or CR) is determined according to RECIST guidelines (version 1.1). In some embodiments, clinical benefit (e.g., SD, PR, and/or CR) is determined according to immune-related RECIST (irRECIST) guidelines. In some embodiments, tumor response may be assessed by either irRECIST or RECIST version 1.1. In some embodiments, tumor response may be assessed by both irRECIST and RECIST version 1.1. As used herein, the term "RECIST guidelines" may refer interchangeably to RECIST 1.0, RECIST 1.1, or irRECIST.

In some embodiments, the patient is receiving or will be receiving additional therapy in combination with the anti-TIM-3 antibody agent. In some embodiments, the additional therapy is radiation therapy, chemotherapy, or immunotherapy. In some embodiments, the additional therapy includes therapy with a composition that delivers a PD-1 inhibitor (e.g., a PD-1 binder) and/or a LAG-3 binder. In some embodiments, the additional PD-1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, TSR-042, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283, MGA012, BI-754091, IBI-308, camreri uzumab (HR-301210), BCD-100, JS-001, CX-072, BGB-A333/AMP-514 (MEDI-0680), AGEN-2034, CS1001, Sym-021, SHR-1316, PF-06801591, LZM009, KN-035, AB122, genolimuzumab (CBT-501), FAZ-053, CK-301, AK 104, GSL-010, PD-1VR, or PD-1FL, or any of the PD-1 antibodies disclosed in WO 2014/179664. In some embodiments, the additional therapy is a PARP inhibitor. In some embodiments, the PARP inhibitor is niraparib, olaparib, rucaparib, talazoparib, and veliparib. In some embodiments, the PARP inhibitor is niraparib.

The present disclosure provides, in some embodiments, a method of treating cancer in a patient in need thereof, comprising administering one or more compositions that deliver an anti-TIM-3 antibody agent in combination with a PD-1 binding agent. In some embodiments, the patient or patient population is receiving a combination therapy that includes administration of an anti-TIM-3 antibody agent and a PD-1 binding agent (e.g., an anti-PD-1 antibody).

In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain having an amino acid sequence comprising SEQ ID NO:1 or SEQ ID NO:7, and an immunoglobulin light chain variable domain having an amino acid sequence comprising SEQ ID NO:2 or SEQ ID NO:8. In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain having an amino acid sequence comprising SEQ ID NO:3, and an immunoglobulin light chain having an amino acid sequence comprising SEQ ID NO:4.

In some embodiments, the PD-1-binding agent comprises an immunoglobulin heavy chain variable domain having an amino acid sequence comprising SEQ ID NO:11 or SEQ ID NO:17, and an immunoglobulin light chain variable domain having an amino acid sequence comprising SEQ ID NO:12 or SEQ ID NO:18 ("PD-1VR"). In some embodiments, the PD-1-binding agent comprises an immunoglobulin heavy chain having an amino acid sequence comprising SEQ ID NO:13, and an immunoglobulin light chain having an amino acid sequence comprising SEQ ID NO:14 ("PD1-FL").

In some embodiments, the anti-TIM-3 antibody agent (e.g., an anti-TIM-3 antibody) is administered at a dose of about 1, 3, or 10 mg/kg. In some embodiments, the anti-TIM-3 antibody agent is administered according to a regimen including a dose of 1, 3, or 10 mg/kg once every two weeks. In some embodiments, the anti-TIM-3 antibody agent is administered according to a regimen including a dose of about 1, 3, or 10 mg/kg once every three weeks. In some embodiments, the anti-TIM-3 antibody agent is administered according to a regimen including a dose of 1, 3, or 10 mg/kg once every four weeks. In some embodiments, the anti-TIM-3 antibody agent is administered at a fixed dose in the range of about 100 mg to 1,500 mg. In some embodiments, the anti-TIM-3 antibody agent is administered at a fixed dose within the range of about 300 mg to 1,000 mg, about 100 mg to about 500 mg, about 100 mg to about 1200 mg, or about 1000 mg to about 1500 mg. In some embodiments, the anti-TIM-3 antibody agent is administered at a fixed dose of about 100, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg. In some embodiments, the anti-TIM-3 antibody agent is administered at a fixed dose of about 100 mg. In some embodiments, the anti-TIM-3 antibody agent is administered at a fixed dose of about 300 mg. In some embodiments, the anti-TIM-3 antibody agent is administered at a fixed dose of about 500 mg. In some embodiments, the anti-TIM-3 antibody drug is administered at a fixed dose of about 900 mg. In some embodiments, the anti-TIM-3 antibody drug is administered at a fixed dose of about 1200 mg. In some embodiments, the anti-TIM-3 antibody drug is administered according to a regimen including a fixed dose once every two weeks (Q2W). In some embodiments, the anti-TIM-3 antibody drug is administered according to a regimen including a fixed dose once every three weeks (Q3W). In some embodiments, the anti-TIM-3 antibody drug is administered according to a regimen including a fixed dose once every four weeks (Q4W).

In some embodiments, the therapeutically effective dose is a dose of about 100 mg to about 1500 mg of anti-TIM-3 antibody, e.g., a dose that is about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200 mg, 1300 mg, 1400 mg, or 1500 mg. In embodiments, the therapeutically effective dose is about 100 mg (e.g., administered Q2W or Q3W). In embodiments, the therapeutically effective dose is about 300 mg (e.g., administered Q2W or Q3W). In embodiments, the therapeutically effective dose is about 500 mg (e.g., administered Q2W or Q3W). In embodiments, the therapeutically effective dose is about 900 mg (e.g., administered Q2W or Q3W). In embodiments, the therapeutically effective dose is about 1200 mg (e.g., administered Q2W or Q3W). In embodiments, the anti-TIM-3 antibody is administered at a dosing interval of once per week (Q1W), once per two weeks (Q2W), once per three weeks (S3W), once per four weeks (Q4W), once per five weeks (Q5W), or once per six weeks (Q6W). In embodiments, the anti-TIM-3 antibody is administered for a period of at least 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 weeks.

In an embodiment, the therapeutically effective dose is about 100 mg and the agent is administered at a dosing interval of once every two weeks. In an embodiment, the therapeutically effective dose is about 100 mg and the agent is administered at a dosing interval of once every three weeks.

In an embodiment, the therapeutically effective dose is about 300 mg and the agent is administered at a dosing interval of once every two weeks. In an embodiment, the therapeutically effective dose is about 300 mg and the agent is administered at a dosing interval of once every three weeks.

In an embodiment, the therapeutically effective dose is about 500 mg and the agent is administered at a dosing interval of once every two weeks. In an embodiment, the therapeutically effective dose is about 500 mg and the agent is administered at a dosing interval of once every three weeks.

In an embodiment, the therapeutically effective dose is about 900 mg and the drug is administered at a dosing interval of once every two weeks. In an embodiment, the therapeutically effective dose is about 900 mg and the drug is administered at a dosing interval of once every three weeks.

In an embodiment, the therapeutically effective dose is about 1200 mg and the drug is administered at a dosing interval of once every two weeks. In an embodiment, the therapeutically effective dose is about 1200 mg and the drug is administered at a dosing interval of once every three weeks.

In embodiments, the dose is administered as a monotherapy (e.g., a therapeutically effective amount of 1200 mg of an anti-TIM-3 antibody administered Q2W or Q3W) or the dose is administered in combination with one or more other therapies. For example, 100 mg or 300 mg of an anti-TIM-3 antibody may be administered in combination with an anti-PD-1 antibody according to the regimens described herein (e.g., 500 mg of an anti-PD-1 antibody administered Q3W for four treatment cycles, followed by 1000 mg of an anti-PD-1 antibody administered Q6W until treatment is discontinued (e.g., due to disease progression)).

In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered at a dose of 0.1, 1, 3, 10, or 20 mg/kg. In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a regimen including a dose of 1, 3, or 10 mg/kg once every two weeks. In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a regimen including a dose of 1, 3, or 10 mg/kg once every three weeks. In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a regimen including a dose of 1, 3, or 10 mg/kg once every four weeks. In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered at a dose of 500 mg/kg. In some embodiments, the PD-1 binding agent (e.g., anti-PD-1 antibody) is administered according to a regimen including a dose of 500 mg/kg once every two weeks. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody) is administered according to a regimen including a dose of 500 mg/kg once every three weeks. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody) is administered according to a regimen including a dose of 500 mg/kg once every four weeks. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody) is administered according to a regimen including a dose of 500 mg/kg once every three weeks for at least one treatment cycle (e.g., at least one, two, three, four treatment cycles), and thereafter. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody) is administered according to a regimen including a dose of 1000 mg/kg once every three weeks. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody) is administered according to a regimen including a dose of 1000 mg/kg once every four weeks. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody) is administered according to a regimen comprising a dose of 1000 mg/kg once every 5 weeks. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody) is administered according to a regimen comprising a dose of 1000 mg/kg once every 6 weeks. In embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody) is administered according to a regimen comprising a dose of 500 mg once every 3 weeks for four treatment cycles, followed by a dose of 1000 mg once every 6 weeks until treatment is discontinued (e.g., due to disease progression). In embodiments, the anti-TIM-3 antibody agent is administered Q2W or Q3W at a dose that is about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, or 1200 mg, or at a dose that is about 1-10 mg/kg (e.g., a dose that is about 1, about 3, or about 10 mg/kg). In embodiments, the anti-TIM-3 antibody agent is administered Q2W or Q3W at a dose that is about 100 mg. In embodiments, the anti-TIM-3 antibody agent is administered Q2W or Q3W at a dose that is about 300 mg.

In an embodiment, the PD-1 inhibitor (e.g., any anti-PD-1 antibody described herein) is administered at a first dose of about 500 mg once every three weeks for three, four, or five cycles, and then at a second dose of about 1000 mg once every six weeks or more (e.g., a second dose of about 1000 mg once every six weeks). In an embodiment, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a flat dose of about 100 mg. In an embodiment, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a flat dose of about 300 mg. In an embodiment, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a flat dose of about 500 mg. In an embodiment, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a flat dose of about 900 mg. In an embodiment, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is administered once every three weeks.

In an embodiment, the PD-1 inhibitor (e.g., any anti-PD-1 antibody described herein) is administered at a first dose of about 500 mg once every three weeks for three cycles, then at a second dose of about 1000 mg once every six weeks or more (e.g., a second dose of about 1000 mg once every six weeks). In an embodiment, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a flat dose of about 100 mg. In an embodiment, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a flat dose of about 300 mg. In an embodiment, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a flat dose of about 500 mg. In an embodiment, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a flat dose of about 900 mg. In an embodiment, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is administered once every three weeks.

In an embodiment, the PD-1 inhibitor (e.g., any anti-PD-1 antibody described herein) is administered at a first dose of about 500 mg once every three weeks for four cycles, then at a second dose of about 1000 mg once every six weeks or more (e.g., a second dose of about 1000 mg once every six weeks). In an embodiment, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a flat dose of about 100 mg. In an embodiment, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a flat dose of about 300 mg. In an embodiment, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a flat dose of about 500 mg. In an embodiment, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a flat dose of about 900 mg. In an embodiment, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is administered once every three weeks.

In an embodiment, the PD-1 inhibitor (e.g., any anti-PD-1 antibody described herein) is administered at a first dose of about 500 mg once every three weeks for five cycles, then at a second dose of about 1000 mg once every six weeks or more (e.g., a second dose of about 1000 mg once every six weeks). In an embodiment, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a flat dose of about 100 mg. In an embodiment, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a flat dose of about 300 mg. In an embodiment, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a flat dose of about 500 mg. In an embodiment, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is a flat dose of about 900 mg. In an embodiment, the therapeutically effective dose of the agent (e.g., an anti-TIM-3 antibody) is administered once every three weeks.

The present disclosure provides, in some embodiments, compositions comprising an anti-TIM-3 antibody agent for use in the treatment of cancer in a selected cancer patient population. In some embodiments, the anti-TIM-3 antibody agent comprises a heavy chain comprising three CDRs having the sequence of SEQ ID NO:21, 22, or 23. In some embodiments, the anti-TIM-3 antibody agent comprises a light chain comprising three CDRs having the sequence of SEQ ID NO:24, 25, or 26. In some embodiments, the anti-TIM-3 antibody agent comprises a heavy chain comprising three CDRs having the sequence of SEQ ID NO:21, 22, or 23; and a light chain comprising three CDRs having the sequence of SEQ ID NO:24, 25, or 26. In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain having an amino acid sequence comprising SEQ ID NO:1 or SEQ ID NO:7. In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin light chain variable domain having an amino acid sequence comprising SEQ ID NO:2 or SEQ ID NO:8. In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain having an amino acid sequence comprising SEQ ID NO:1 or SEQ ID NO:7, and an immunoglobulin light chain variable domain having an amino acid sequence comprising SEQ ID NO:2 or SEQ ID NO:8. In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain having an amino acid sequence comprising SEQ ID NO:3. In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin light chain having an amino acid sequence comprising SEQ ID NO:4. In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain having an amino acid sequence comprising SEQ ID NO:3, and an immunoglobulin light chain having an amino acid sequence comprising SEQ ID NO:4.

In some embodiments, the patients in the cancer patient population each have a tumor. In some embodiments, the patients in the cancer patient population each have a solid tumor. In some embodiments, at least a portion of the patients in the cancer patient population have an advanced stage solid tumor. In some embodiments, at least a portion of the patients in the cancer patient population have a metastatic solid tumor. In some embodiments, the patients have an MSI-H solid tumor. In some embodiments, the patients in the cancer patient population each have a cancer such as non-small cell lung cancer (NSCLC), hepatocellular carcinoma, renal cancer, melanoma, cervical cancer, colorectal cancer, squamous cell carcinoma of the anogenital region (e.g., squamous cell carcinoma of the anus, penis, cervix, vagina, or vulva), head and neck cancer, triple negative breast cancer, ovarian cancer, or endometrial cancer.

In an embodiment, the patient has lung cancer (e.g., non-small cell lung cancer (NSCLC)). In an embodiment, the patient has melanoma.

In some embodiments, the patient has a cancer associated with a POLE (DNA polymerase epsilon) or POLD (DNA polymerase delta) mutation. In some embodiments, the POLE or POLD mutation is in the exonuclease domain. In some embodiments, the POLE or POLD mutation is a germline mutation. In some embodiments, the POLE or POLD mutation is a sporadic mutation. In some embodiments, the methods described herein further comprise initially identifying a patient having a cancer with a POLE or POLD mutation. In some embodiments, the POLE or POLD mutation is identified using sequencing.

In some embodiments, the patients in the cancer patient population each have a cancer with microsatellite instability. In some embodiments, the microsatellite instability is considered high frequency when it is significantly higher than the instability observed in control cells. In some embodiments, the microsatellite instability is low frequency MSI (MSI-L). In some embodiments, the microsatellite instability is microsatellite stable (e.g., MSS state). In some embodiments, the patients have advanced stage solid tumors with microsatellite instability.

In some embodiments, the patients in the cancer patient population each have a hematological cancer, such as diffuse large B-cell lymphoma ("DLBCL"), Hodgkin's lymphoma ("HL"), non-Hodgkin's lymphoma ("NHL"), follicular lymphoma ("FL"), acute myeloid leukemia ("AML"), acute lymphoblastic leukemia ("ALL"), or multiple myeloma ("MM"). In some embodiments, the patients in the cancer patient population each have a hematological cancer with microsatellite instability.

In some embodiments, at least some of the patients in the cancer patient population have been previously treated with one or more cancer treatment modalities. In some embodiments, at least some of the patients in the cancer patient population have been previously treated with one or more of radiation therapy, chemotherapy, or immunotherapy. In some embodiments, at least some of the patients in the cancer patient population have been previously treated with chemotherapy (e.g., platinum-based chemotherapy).

In some embodiments, at least some patients in the cancer patient population have not been previously treated with one or more cancer treatment modalities.

The disclosure provides, in some embodiments, a combination therapy for use in treating cancer in a select cancer patient population, the combination therapy comprising administering an anti-TIM-3 antibody agent and a PD-1 binding agent.
The present invention provides, for example, the following items.
(Item 1)
1. A method of treating a disorder in a subject responsive to T cell immunoglobulin and mucin protein 3 (TIM-3) inhibition, comprising administering a therapeutically effective dose of an agent capable of inhibiting TIM-3 signaling, wherein the therapeutically effective dose is about 1, 3, or 10 mg/kg; a flat dose between about 100 and 1500 mg; a flat dose of about 100 mg; a flat dose of about 200 mg; a flat dose of about 300 mg; a flat dose of about 400 mg; a flat dose of about 500 mg; a flat dose of about 600 mg; a flat dose of about 700 mg; a flat dose of about 800 mg; a flat dose of about 900 mg; a flat dose of about 1000 mg; a flat dose of about 1100 mg; a flat dose of about 1200 mg; a flat dose of about 1300 mg; a flat dose of about 1400 mg; a flat dose of about 1500 mg; about 1 mg/kg; about 3 mg/kg; or about 10 mg/kg.
(Item 2)
A method of increasing T cell activation or T cell effector function in a subject responsive to T cell immunoglobulin and mucin protein 3 (TIM-3) inhibition, comprising administering a therapeutically effective dose of an agent capable of inhibiting TIM-3 signaling, wherein the therapeutically effective dose is about 1, 3, or 10 mg/kg; a flat dose between about 100-1500 mg; a flat dose of about 100 mg; a flat dose of about 200 mg; a flat dose of about 300 mg; a flat dose of 400 mg; a flat dose of about 500 mg; a flat dose of about 600 mg; a flat dose of about 700 mg; a flat dose of about 800 mg; a flat dose of about 900 mg; a flat dose of about 1000 mg; a flat dose of about 1100 mg; a flat dose of about 1200 mg; a flat dose of about 1300 mg; a flat dose of about 1400 mg; a flat dose of about 1500 mg; about 1 mg/kg; about 3 mg/kg; or about 10 mg/kg.
(Item 3)
A method of reducing tumors or inhibiting tumor cell growth in a subject responsive to T cell immunoglobulin and mucin protein 3 (TIM-3) inhibition, comprising administering a therapeutically effective dose of an agent capable of inhibiting TIM-3 signaling, wherein the therapeutically effective dose is about 1, 3, or 10 mg/kg; a flat dose between about 100-1500 mg; a flat dose of about 100 mg; a flat dose of about 200 mg; a flat dose of about 300 mg; a flat dose of about 400 mg; mg flat dose; about 500 mg flat dose; about 600 mg flat dose; about 700 mg flat dose; about 800 mg flat dose; about 900 mg flat dose; about 1000 mg flat dose; about 1100 mg flat dose; about 1200 mg flat dose; about 1300 mg flat dose; about 1400 mg flat dose; about 1500 mg flat dose; about 1 mg/kg; about 3 mg/kg; or about 10 mg/kg.
(Item 4)
1. A method of inducing an immune response in a subject responsive to T cell immunoglobulin and mucin protein 3 (TIM-3) inhibition, comprising administering a therapeutically effective dose of an agent capable of inhibiting TIM-3 signaling, wherein the therapeutically effective dose is about 1, 3, or 10 mg/kg; a flat dose between about 100-1500 mg; a flat dose of about 100 mg; a flat dose of about 200 mg; a flat dose of about 300 mg; a flat dose of about 400 mg; a flat dose of about 500 mg; a flat dose of about 600 mg; a flat dose of about 700 mg; a flat dose of about 800 mg; a flat dose of about 900 mg; a flat dose of about 1000 mg; a flat dose of about 1100 mg; a flat dose of about 1200 mg; a flat dose of about 1300 mg; a flat dose of about 1400 mg; a flat dose of about 1500 mg; about 1 mg/kg; about 3 mg/kg; or about 10 mg/kg.
(Item 5)
A method of enhancing an immune response or increasing immune cell activity in a subject responsive to T cell immunoglobulin and mucin protein 3 (TIM-3) inhibition, comprising administering a therapeutically effective dose of an agent capable of inhibiting TIM-3 signaling, wherein the therapeutically effective dose is about 1, 3, or 10 mg/kg; a flat dose between about 100-1500 mg; a flat dose of about 100 mg; a flat dose of about 200 mg; a flat dose of about 300 mg; a flat dose of about 4 a flat dose of about 100 mg; a flat dose of about 500 mg; a flat dose of about 600 mg; a flat dose of about 700 mg; a flat dose of about 800 mg; a flat dose of about 900 mg; a flat dose of about 1000 mg; a flat dose of about 1100 mg; a flat dose of about 1200 mg; a flat dose of about 1300 mg; a flat dose of about 1400 mg; a flat dose of about 1500 mg; about 1 mg/kg; about 3 mg/kg; or about 10 mg/kg.
(Item 6)
6. The method of claim 5, wherein the immune response is a humoral or cell-mediated immune response.
(Item 7)
7. The method of claim 6, wherein the immune response is a CD4 or CD8 T cell response.
(Item 8)
7. The method of claim 6, wherein the immune response is a B cell response.
(Item 9)
Item 10. The method of any one of items 1 to 8, wherein the therapeutically effective dose is about 1 mg/kg.
11. The method of any one of claims 1 to 8, wherein the therapeutically effective dose is about 3 mg/kg.
9. The method of any one of items 1 to 8, wherein the therapeutically effective dose is about 10 mg/kg.
(Item 12)
9. The method of any one of items 1 to 8, wherein the therapeutically effective dose is a flat dose of about 100 mg.
(Item 13)
9. The method of any one of items 1 to 8, wherein the therapeutically effective dose is a flat dose of about 200 mg.
(Item 14)
9. The method of any one of items 1 to 8, wherein the therapeutically effective dose is a flat dose of about 300 mg.
(Item 15)
9. The method of any one of items 1 to 8, wherein the therapeutically effective dose is a flat dose of about 400 mg.
(Item 16)
9. The method of any one of items 1 to 8, wherein the therapeutically effective dose is a flat dose of about 500 mg.
(Item 17)
9. The method of any one of items 1 to 8, wherein the therapeutically effective dose is a flat dose of about 600 mg.
(Item 18)
9. The method of any one of items 1 to 8, wherein the therapeutically effective dose is a flat dose of about 700 mg.
(Item 19)
9. The method of any one of items 1 to 8, wherein the therapeutically effective dose is a flat dose of about 800 mg.
(Item 20)
9. The method of any one of items 1 to 8, wherein the therapeutically effective dose is a flat dose of about 900 mg.
(Item 21)
9. The method of any one of items 1 to 8, wherein the therapeutically effective dose is a flat dose of about 1000 mg.
(Item 22)
9. The method of any one of items 1 to 8, wherein the therapeutically effective dose is a flat dose of about 1100 mg.
(Item 23)
9. The method of any one of items 1 to 8, wherein the therapeutically effective dose is a flat dose of about 1200 mg.
(Item 24)
9. The method of any one of items 1 to 8, wherein the therapeutically effective dose is a flat dose of about 1300 mg.
(Item 25)
9. The method of any one of items 1 to 8, wherein the therapeutically effective dose is a flat dose of about 1400 mg.
(Item 26)
9. The method of any one of items 1 to 8, wherein the therapeutically effective dose is a flat dose of about 1500 mg.
(Item 27)
27. The method of any one of items 1-26, wherein the agent is administered at a dosing interval of once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks.
(Item 28)
28. The method of claim 27, wherein the agent is administered at a dosing interval of once every three weeks.
(Item 29)
29. The method of claim 28, wherein the therapeutically effective dose is a flat dose of about 100 mg, 300 mg, 500 mg, or 900 mg.
(Item 30)
30. The method of any one of items 1-29, wherein the agent is administered for a period of time sufficient to achieve a clinical benefit.
(Item 31)
31. The method of item 30, wherein said clinical benefit is stable disease ("SD"), partial response ("PR"), and/or complete response ("CR").
(Item 32)
32. The method of item 31, wherein said PR or CR is determined according to Response Evaluation Criteria in Solid Tumors (RECIST).
(Item 33)
33. The method of any one of items 30-32, wherein the agent is administered for a longer period to maintain clinical benefit.
(Item 34)
34. The method of any one of items 1-33, wherein the agent is administered for a period of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 weeks or more.
(Item 35)
35. The method of any one of items 1 to 34, wherein the disorder is a T cell dysfunction disorder.
(Item 36)
36. The method of any one of items 1 to 35, wherein the disorder is cancer.
(Item 37)
The cancer is:
i) Cancers with high tumor mutation burden (TMB),
ii) cancers that are microsatellite stable (MSS);
iii) Cancers characterized by microsatellite instability;
iv) cancers with microsatellite instability high status (MSI-H);
v) cancers with microsatellite instability low status (MSI-L);
vi) Cancer with high TMB and MSI-H;
vii) Cancers with high TMB and MSI-L or MSS;
viii) Cancers with defective DNA mismatch repair systems;
ix) Cancers with defects in DNA mismatch repair genes;
x) hypermutable cancer,
xi) cancers containing mutations in polymerase delta (POLD);
xii) cancers containing mutations in polymerase epsilon (POLE);
xiii) Cancers with homology directed repair deficiency/homologous repair deficiency ("HRD");
xiv) adenocarcinoma, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, testicular cancer, primary peritoneal cancer, colon cancer, colorectal cancer, gastric cancer, small intestine cancer, squamous cell carcinoma of the anus, squamous cell carcinoma of the penis, squamous cell carcinoma of the cervix, squamous cell carcinoma of the vagina, squamous cell carcinoma of the vulva, soft tissue sarcoma, melanoma, renal cell carcinoma, lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung, gastric cancer, bladder cancer, gallbladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, Head and neck cancer, squamous cell carcinoma of the head and neck, prostate cancer, cancer of the pancreas, mesothelioma, Merkel cell carcinoma, sarcoma, glioblastoma, blood cancer, multiple myeloma, B cell lymphoma, T cell lymphoma, Hodgkin lymphoma/primary mediastinal B cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, acute lymphocytic leukemia, non-Hodgkin lymphoma, neuroblastoma, central nervous system tumors, diffuse intrinsic pontine glioma (DIPG), Ewing sarcoma, embryonal rhabdomyosarcoma, osteosarcoma, or Wilms tumor, or xiii) The method of claim 36, wherein the cancer of xiv) is any of MSS or MSI-L, characterized by microsatellite instability, MSI-H, has high TMB, has high TMB and MSS or MSI-L, has high TMB and MSI-H, has a defective DNA mismatch repair system, has defects in DNA mismatch repair genes, is a hypermutable cancer, is an HRD cancer, contains a mutation in polymerase delta (POLD), or contains a mutation in polymerase epsilon (POLE).
(Item 38)
37. The method of claim 36, wherein the cancer is a cancer with homology directed repair deficiency/homology directed repair deficiency ("HRD").
(Item 39)
36. The method of claim 35, wherein the cancer is endometrial cancer, optionally MSI-H or MSS/MSI-L endometrial cancer.
(Item 40)
36. The method of claim 35, wherein the cancer is an MSI-H cancer comprising a mutation in POLE or POLD, and optionally an MSI-H non-endometrial cancer comprising a mutation in POLE or POLD.
(Item 41)
36. The method of claim 35, wherein the cancer is breast cancer, optionally triple-negative breast cancer (TNBC).
(Item 42)
36. The method of claim 35, wherein the cancer is ovarian cancer, optionally epithelial ovarian cancer.
(Item 43)
36. The method of claim 35, wherein the cancer is lung cancer, optionally non-small cell lung cancer.
(Item 44)
36. The method of claim 35, wherein the cancer is melanoma.
(Item 45)
36. The method of claim 35, wherein the cancer is colorectal cancer.
(Item 46)
36. The method of claim 35, wherein the cancer is squamous cell carcinoma of the anus, squamous cell carcinoma of the penis, squamous cell carcinoma of the cervix, squamous cell carcinoma of the vagina, or squamous cell carcinoma of the vulva.
(Item 47)
36. The method of claim 35, wherein the cancer is acute myeloid leukemia.
(Item 48)
36. The method of claim 35, wherein the cancer is acute lymphoblastic leukemia.
(Item 49)
36. The method of claim 35, wherein the cancer is non-Hodgkin's lymphoma.
(Item 50)
36. The method of claim 35, wherein the cancer is Hodgkin's lymphoma.
(Item 51)
36. The method of claim 35, wherein the cancer is neuroblastoma.
(Item 52)
36. The method of claim 35, wherein the cancer is a central nervous system tumor.
(Item 53)
36. The method of claim 35, wherein the cancer is diffuse intrinsic pontine glioma (DIPG).
(Item 54)
36. The method of claim 35, wherein the cancer is Ewing's sarcoma.
(Item 55)
36. The method of claim 35, wherein the cancer is embryonal rhabdomyosarcoma.
(Item 56)
36. The method of claim 35, wherein the cancer is osteosarcoma.
(Item 57)
36. The method of claim 35, wherein the cancer is Wilms' tumor.
(Item 58)
36. The method of claim 35, wherein the cancer is a soft tissue sarcoma.
(Item 59)
49. The method of claim 48, wherein the cancer is leiomyosarcoma.
(Item 60)
60. The method of any one of items 1 to 59, wherein the subject has been or will be further administered an immune checkpoint inhibitor, such that the mammal receives both the agent and the immune checkpoint inhibitor.
(Item 61)
61. The method of claim 60, comprising administering one, two, or three immune checkpoint inhibitors.
(Item 62)
62. The method of claim 60 or 61, wherein the immune checkpoint inhibitor is an agent that inhibits programmed cell death protein 1 (PD-1) signaling, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and ITIM domain (TIGIT), indoleamine 2,3-dioxygenase (IDO), or colony-stimulating factor 1 receptor (CSF1R).
(Item 63)
63. The method of claim 62, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.
(Item 64)
64. The method of claim 63, wherein the PD-1 inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, a toxin, or a PD-1 binding agent.
(Item 65)
65. The method of claim 63 or 64, wherein the PD-1 inhibitor is a PD-1 binding agent.
(Item 66)
66. The method of claim 65, wherein the PD-1 binding agent is an antibody, antibody conjugate, or antigen-binding fragment thereof.
(Item 67)
The PD-1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283, MGA012, BI-754091, IBI-308, camrelizumab (HR-301210), BCD-100, JS-001, CX-072, AMP-514/MEDI-0680, AGEN-2034, CS1001, TSR-042, Sym-021, PF-06801591, LZM009, KN-035, AB122, genolizumab (CBT-501), AK 104, or GLS-010, or a derivative thereof.
(Item 68)
65. The method of claim 63 or 64, wherein the PD-1 inhibitor is a PD-L1/L2 binding agent.
(Item 69)
70. The method of claim 68, wherein the PD-L1/L2 binding agent is an antibody, an antibody conjugate, or an antigen-binding fragment thereof.
(Item 70)
70. The method of claim 69, wherein the PD-L1/L2 binding agent is durvalumab, atezolizumab, avelumab, BGB-A333, SHR-1316, FAZ-053, CK-301, or PD-L1 miramolecule, or a derivative thereof.
(Item 71)
66. The method of any one of claims 63-65, wherein the PD-1 binding agent is an anti-PD-1 antibody comprising a heavy chain comprising SEQ ID NO:13 and a light chain of SEQ ID NO:14.
(Item 72)
72. The method of any one of items 63 to 71, wherein the PD-1 inhibitor is administered to the subject periodically at a dose of about 500 mg or 1000 mg.
(Item 73)
73. The method of claim 72, wherein the PD-1 inhibitor is administered to the subject periodically at a dose of about 500 mg.
(Item 74)
74. The method of claim 72 or 73, wherein the PD-1 inhibitor is administered to the subject once every three weeks.
(Item 75)
75. The method of any one of items 71 to 74, wherein the PD-1 inhibitor is administered for 2, 3, 4, 5, 6 or more cycles.
(Item 76)
76. The method of claim 75, wherein the PD-1 inhibitor is administered for 3, 4, or 5 cycles.
(Item 77)
73. The method of claim 72, wherein the PD-1 inhibitor is administered to the subject periodically at a dose of about 1000 mg.
(Item 78)
80. The method of claim 72 or 77, wherein the PD-1 inhibitor is administered to the subject one or more times every six weeks.
(Item 79)
79. The method of claim 78, wherein the PD-1 inhibitor is administered to the subject once every six weeks.
(Item 80)
79. The method of claim 78, wherein the PD-1 inhibitor is administered at a first dose of about 500 mg once every 3 weeks for 3, 4, or 5 cycles, followed by a second dose of about 1000 mg once or more every 6 weeks.
(Item 81)
81. The method of item 80, wherein the PD-1 inhibitor is administered at a first dose of about 500 mg once every 3 weeks for 3, 4, or 5 cycles, followed by a second dose of about 1000 mg once every 6 weeks.
(Item 82)
81. The method of item 80, wherein the PD-1 inhibitor is administered at a first dose of about 500 mg once every three weeks for three cycles, and then at a second dose of about 1000 mg once or more every six weeks.
(Item 83)
81. The method of item 80, wherein the PD-1 inhibitor is administered at a first dose of about 500 mg once every three weeks for four cycles, followed by a second dose of about 1000 mg once or more every six weeks.
(Item 84)
81. The method of item 80, wherein the PD-1 inhibitor is administered at a first dose of about 500 mg once every three weeks for five cycles, followed by a second dose of about 1000 mg once or more every six weeks.
(Item 85)
75. The method of any one of items 82-74, wherein the second dose of 1000 mg is administered once every six weeks.
(Item 86)
62. The method of claim 60 or 61, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.
(Item 87)
87. The method of claim 86, wherein the CTLA-4 inhibitor is a small molecule, a nucleic acid, a polypeptide (eg, an antibody), a carbohydrate, a lipid, a metal, a toxin, or a CTLA-4 binding agent.
(Item 88)
88. The method of claim 87, wherein the CTLA-4 inhibitor is a CTLA-4 binding agent.
(Item 89)
90. The method of claim 88, wherein the CTLA-4 binding agent is an antibody, an antibody conjugate, or an antigen-binding fragment thereof.
(Item 90)
62. The method of claim 60 or 61, wherein the immune checkpoint inhibitor is a LAG-3 inhibitor.
(Item 91)
91. The method of claim 90, wherein the LAG-3 inhibitor is a small molecule, a nucleic acid, a polypeptide (eg, an antibody), a carbohydrate, a lipid, a metal, a toxin, or a LAG-3 binding agent.
(Item 92)
92. The method of claim 91, wherein the LAG-3 inhibitor is a LAG-3 binding agent.
(Item 93)
93. The method of claim 92, wherein the LAG-3 binding agent is an antibody, antibody conjugate, or antigen-binding fragment thereof.
(Item 94)
62. The method of claim 60 or 61, wherein the immune checkpoint inhibitor is a TIGIT inhibitor.
(Item 95)
95. The method of claim 94, wherein the TIGIT inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, a toxin, or a TIGIT binding agent.
(Item 96)
96. The method of claim 95, wherein the TIGIT inhibitor is a TIGIT binding agent.
(Item 97)
97. The method of claim 96, wherein the TIGIT binding agent is an antibody, an antibody conjugate, or an antigen-binding fragment thereof.
(Item 98)
62. The method of claim 60 or 61, wherein the immune checkpoint inhibitor is an IDO inhibitor.
(Item 99)
99. The method of claim 98, wherein the IDO inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, a toxin, or an IDO binding agent.
(Item 100)
100. The method of claim 99, wherein the IDO inhibitor is a small molecule.
(Item 101)
100. The method of claim 99, wherein the IDO inhibitor is an IDO binding agent, optionally an IDO binding agent that is an antibody, antibody conjugate, or antigen-binding fragment thereof.
(Item 102)
62. The method of claim 60 or 61, wherein the immune checkpoint inhibitor is a CSF1R inhibitor.
(Item 103)
103. The method of claim 102, wherein the CSF1R inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, a toxin, or an IDO binding agent.
(Item 104)
104. The method of claim 103, wherein the CSF1R inhibitor is a small molecule.
(Item 105)
104. The method of claim 103, wherein the CSF1R inhibitor is a CSF1R binding agent, optionally a CSF1R binding agent that is an antibody, an antibody conjugate, or an antigen-binding fragment thereof.
(Item 106)
106. The method of any one of items 60 to 105, comprising administering at least two of the immune checkpoint inhibitors.
(Item 107)
107. The method of claim 106, further comprising administering a third checkpoint inhibitor.
(Item 108)
109. The method of claim 106 or 107, wherein the subject is treated with each of the agent, a PD-1 inhibitor, and a LAG-3 inhibitor, such that the subject receives all three.
109. The method of claim 108, further comprising treating the subject with a CTLA-4 inhibitor, such that the subject receives all four.
(Item 110)
110. The method of any one of items 1 to 109, wherein the subject has been or will be administered an agent that inhibits poly(ADP-ribose) polymerase (PARP).
(Item 111)
111. The method of claim 110, wherein the agent that inhibits PARP is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin.
(Item 112)
The drug that inhibits PARP is: ABT-767, AZD 2461, BGB-290, BGP 15, CEP 8983, CEP 9722, DR 2313, E7016, E7449, fluzoparib (SHR 3162), IMP 4297, INO1001, JPI 289, JPI 547, monoclonal antibody B3-LysPE40 conjugate, MP 124, niraparib (ZEJULA) (MK-4827), NU 1025, NU 1064, NU 1076, NU1085, olaparib (AZD2281), ONO2231, PD 128763, R 503, R554, rucaparib (RUBRACA) (AG-014699, PF-01367338), SBP 101, SC 101914, simmiparib, talazoparib (BMN-673), veliparib (ABT-888), WW 46, 2-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-ol, and salts or derivatives thereof.
(Item 113)
113. The method of any one of items 110 to 112, wherein the subject is treated with each of the agent, a PD-1 inhibitor, and an inhibitor that inhibits PARP, such that the subject receives all three.
(Item 114)
114. The method of claim 113, further comprising treating the subject with a LAG-3 inhibitor such that the mammal receives all four.
(Item 115)
115. The method of any one of items 60 to 114, wherein the therapeutically effective dose of the agent is a flat dose of about 100 mg.
(Item 116)
115. The method of any one of items 60 to 114, wherein the therapeutically effective dose of the agent is a flat dose of about 300 mg.
(Item 117)
115. The method of any one of items 60 to 114, wherein the therapeutically effective dose of the agent is a flat dose of about 500 mg.
(Item 118)
115. The method of any one of items 60 to 114, wherein the therapeutically effective dose of the agent is a flat dose of about 900 mg.
(Item 119)
119. The method of any one of items 1 to 118, wherein the subject is resistant to treatment with a PD-1 inhibitor.
(Item 120)
120. The method of any one of items 1 to 119, wherein the subject is refractory to treatment with a PD-1 inhibitor.
(Item 121)
121. The method of any one of items 1 to 120, wherein the subject is sensitized to treatment with a PD-1 inhibitor.
(Item 122)
122. The method of any one of items 1-121, wherein the subject comprises exhausted immune cells.
(Item 123)
123. The method of claim 122, wherein the exhausted immune cells are exhausted T cells.
(Item 124)
124. The method of any one of items 1 to 123, wherein the subject is a human.
(Item 125)
125. The method of any one of items 1-124, wherein the subject has previously been treated with one or more different cancer treatment modalities.
(Item 126)
126. The method of claim 125, wherein the subject has previously been treated with one or more of surgery, radiation therapy, chemotherapy, or immunotherapy.
(Item 127)
127. The method of claim 125 or 126, wherein the subject has previously been treated with a cytotoxic therapy.
(Item 128)
128. The method of any one of items 125 to 127, wherein the subject has previously been treated with chemotherapy.
(Item 129)
129. The method of any one of items 1 to 128, further comprising administering another therapeutic agent or treatment.
(Item 130)
130. The method of claim 129, further comprising administering one or more of surgery, radiation therapy, chemotherapy, immunotherapy, an anti-angiogenic agent, or an anti-inflammatory agent.
(Item 131)
130. The method of claim 129, further comprising administering chemotherapy.
(Item 132)
132. The method of any one of the preceding claims, wherein the agent is a TIM-3 binding agent.
(Item 133)
The method of claim 132, wherein the TIM-3-binding agent is an antibody, an antibody conjugate, or an antigen-binding fragment thereof.
(Item 134)
134. The method of claim 133, wherein the TIM-3 binding agent is an antibody.
(Item 135)
135. The method of claim 132, wherein the TIM-3-binding agent comprises a heavy chain comprising one or more CDR sequences having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:21, 22, or 23.
(Item 136)
136. The method of claim 135, wherein the TIM-3-binding agent comprises a heavy chain comprising two or three CDRs having the sequence of SEQ ID NO:21, 22, or 23.
(Item 137)
137. The method of any one of paragraphs 132-136, wherein the TIM-3-binding agent comprises a light chain comprising one or more CDR sequences having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:24, 25, or 26.
(Item 138)
138. The method of claim 137, wherein the TIM-3-binding agent comprises a light chain comprising two or three CDRs having the sequence of SEQ ID NO:24, 25, or 26.
(Item 139)
135. The method of any one of paragraphs 132-134, wherein the TIM-3-binding agent comprises a heavy chain comprising one or more CDR sequences selected from SEQ ID NOs: 21, 22, or 23; and/or a light chain variable region comprising one or more CDR sequences selected from SEQ ID NOs: 24, 25, or 26.
(Item 140)
140. The method of claim 139, wherein the TIM-3-binding agent comprises a heavy chain comprising three CDRs having the sequence of SEQ ID NO:21, 22, or 23; and/or a light chain comprising three CDRs having the sequence of SEQ ID NO:24, 25, or 26.
(Item 141)
The TIM-3 binding agent comprises:
135. The method of any one of items 132 to 134, comprising an immunoglobulin heavy chain variable domain comprising an amino acid sequence having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:1 or SEQ ID NO:7; and/or an immunoglobulin light chain variable domain comprising an amino acid sequence having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:2 or SEQ ID NO:8.
(Item 142)
142. The method of claim 141, wherein the TIM-3-binding agent comprises an immunoglobulin heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:7, and an immunoglobulin light chain variable domain comprising the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:8.
(Item 143)
135. The method of any one of paragraphs 132-134, wherein the TIM-3-binding agent comprises an immunoglobulin heavy chain polypeptide comprising an amino acid sequence having about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:3.
(Item 144)
144. The method of any one of paragraphs 132-134 and 143, wherein the TIM-3-binding agent comprises an immunoglobulin light chain polypeptide comprising an amino acid sequence having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:4.
(Item 145)
135. The method of any one of paragraphs 132 to 134, wherein the TIM-3-binding agent comprises a heavy chain polypeptide comprising SEQ ID NO:3 and a light chain polypeptide of SEQ ID NO:4.
(Item 146)
146. The method of any one of items 132-145, wherein the TIM-3 binding agent is administered in an amount of about 1 mg/kg, 3 mg/kg, or 10 mg/kg; or in an amount of about 100 mg flat dose; about 200 mg flat dose; about 300 mg flat dose; about 400 mg flat dose; about 500 mg flat dose; about 600 mg flat dose; about 700 mg flat dose; about 800 mg flat dose; about 900 mg flat dose; about 1000 mg flat dose; about 1100 mg flat dose; about 1200 mg flat dose; about 1300 mg flat dose; about 1400 mg flat dose; or about 1500 mg flat dose.
(Item 147)
148. The method of claim 146, wherein the TIM-3 binding agent is administered at a flat dose of about 100 mg, a flat dose of about 200 mg, a flat dose of about 300 mg, a flat dose of about 400 mg, a flat dose of about 500 mg, a flat dose of about 600 mg, a flat dose of about 700 mg, a flat dose of about 800 mg, or a flat dose of about 900 mg.
147. The method of claim 146, wherein the TIM-3 binding agent is administered once every two weeks, once every three weeks, or once every four weeks.
(Item 149)
149. The method of any one of items 132-148, wherein the TIM-3 binding agent is administered once every three weeks.
(Item 150)
150. The method of any one of the preceding claims, wherein the agent is administered intravenously.
(Item 151)
151. The method of claim 150, wherein the agent is administered by intravenous infusion.
(Item 152)
1. A method for treating cancer, comprising:
administering to a patient in need of treatment a therapeutically effective dose of an anti-T cell immunoglobulin and mucin domain-3 (TIM-3) antibody at a dosing interval for a period of time sufficient to achieve clinical benefit;
The method, wherein the antibody comprises a heavy chain comprising three CDRs having the sequence of SEQ ID NO: 21, 22, or 23; and/or a light chain comprising three CDRs having the sequence of SEQ ID NO: 24, 25, or 26.
(Item 153)
1. A method for treating cancer, comprising:
administering to a patient in need of treatment a therapeutically effective dose of an anti-T cell immunoglobulin and mucin domain-3 (TIM-3) antibody at a dosing interval for a period of time sufficient to achieve clinical benefit;
The method, wherein the anti-TIM-3 antibody comprises an immunoglobulin heavy chain variable domain comprising SEQ ID NO:1 or SEQ ID NO:7, and an immunoglobulin light chain variable domain comprising SEQ ID NO:2 or SEQ ID NO:8.
(Item 154)
1. A method for treating cancer, comprising:
administering to a patient in need of treatment a therapeutically effective dose of an anti-T cell immunoglobulin and mucin domain-3 (TIM-3) antibody at a dosing interval for a period of time sufficient to achieve clinical benefit;
The method, wherein the anti-TIM-3 antibody comprises a heavy chain polypeptide comprising SEQ ID NO:3 and a light chain polypeptide comprising SEQ ID NO:4.
(Item 155)
155. The method of any one of paragraphs 152-154, wherein said clinical benefit is stable disease ("SD"), partial response ("PR"), and/or complete response ("CR").
(Item 156)
156. The method of any one of items 152 to 155, wherein said PR or CR is determined according to Response Evaluation Criteria in Solid Tumors (RECIST).
(Item 157)
158. The method of any one of items 152 to 157, wherein the patient has a cancer associated with a POLE (DNA polymerase epsilon) or POLD (DNA polymerase delta) mutation.
(Item 158)
158. The method of claim 157, wherein the POLE or POLD mutation is in the exonuclease domain.
(Item 159)
159. The method of claim 157 or 158, wherein the POLE or POLD mutation is a germline mutation.
(Item 160)
160. The method of claim 157 or 159, wherein the POLE or POLD mutation is a sporadic mutation.
(Item 161)
161. The method of any one of items 157 to 160, further comprising the step of initially identifying a patient having a cancer that has a POLE or POLD mutation.
(Item 162)
162. The method of claim 161, wherein the POLE or POLD mutation is identified using sequencing.
(Item 163)
163. The method of any one of items 152-162, wherein the patient has a cancer with microsatellite instability.
(Item 164)
164. The method of claim 163, wherein the patient has an MSI-H cancer.
(Item 165)
165. The method of claim 164, wherein the cancer is an MSI-H cancer comprising a mutation in POLE or POLD, and optionally an MSI-H non-endometrial cancer comprising a mutation in POLE or POLD.
(Item 166)
165. The method of claim 164, wherein the patient has an MSI-L cancer.
(Item 167)
163. The method of any one of items 152-162, wherein the patient has a microsatellite stable (MSS) cancer.
(Item 168)
168. The method of any one of items 152 to 167, wherein the patient has a solid tumor.
(Item 169)
169. The method of claim 168, wherein the patient has an advanced stage solid tumor.
(Item 170)
169. The method of claim 168, wherein the patient has a metastatic solid tumor.
(Item 171)
171. The method of any one of paragraphs 152-170, wherein said patient has a cancer selected from head and neck cancer, lung cancer, kidney cancer, bladder cancer, melanoma, Merkel cell carcinoma, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, breast cancer, prostate cancer, oral adenocarcinoma, thymoma, adrenal cortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendix cancer, urothelial cell carcinoma, squamous cell carcinoma, soft tissue sarcoma, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma, Hodgkin's lymphoma, neuroblastoma, central nervous system tumor, diffuse intrinsic pontine glioma (DIPG), Ewing's sarcoma, embryonal rhabdomyosarcoma (ERS), osteosarcoma, or Wilms' tumor.
(Item 172)
172. The method of any one of items 152 to 171, wherein the cancer has a homology directed repair deficiency/homology directed repair deficiency ("HRD").
(Item 173)
172. The method of claim 171, wherein the patient has endometrial cancer.
(Item 174)
174. The method of claim 173, wherein the patient has endometrial cancer with microsatellite instability.
(Item 175)
174. The method of claim 173, wherein the patient has MSI-H endometrial cancer.
(Item 176)
174. The method of claim 173, wherein the patient has MSS/MSI-L endometrial cancer.
(Item 177)
172. The method of claim 171, wherein the patient has breast cancer.
(Item 178)
178. The method of claim 177, wherein the patient has triple-negative breast cancer (TNBC).
(Item 179)
172. The method of claim 171, wherein the patient has ovarian cancer.
(Item 180)
180. The method of claim 179, wherein the ovarian cancer is epithelial ovarian cancer.
(Item 181)
172. The method of claim 171, wherein the patient has lung cancer.
(Item 182)
182. The method of claim 181, wherein the lung cancer is non-small cell lung cancer (NSCLC).
(Item 183)
172. The method of claim 171, wherein the patient has melanoma.
(Item 184)
172. The method of claim 171, wherein the patient has colorectal cancer.
(Item 185)
172. The method of claim 171, wherein the patient has squamous cell carcinoma.
(Item 186)
186. The method of claim 185, wherein the squamous cell carcinoma is squamous cell carcinoma of the anus, squamous cell carcinoma of the penis, squamous cell carcinoma of the cervix, squamous cell carcinoma of the vagina, or squamous cell carcinoma of the vulva.
(Item 187)
172. The method of claim 171, wherein the patient has a soft tissue sarcoma.
(Item 188)
188. The method of claim 187, wherein the patient has leiomyosarcoma.
(Item 189)
168. The method of any one of items 152 to 167, wherein the patient has a hematological cancer.
(Item 190)
190. The method of claim 189, wherein the hematological cancer is DLBCL, HL, NHL, FL, AML, ALL, or MM.
(Item 191)
191. The method of any one of items 152-190, wherein the patient has not been previously treated with a cancer treatment modality.
(Item 192)
191. The method of any one of items 152-190, wherein the patient has previously been treated with one or more different cancer treatment modalities.
(Item 193)
200. The method of claim 192, wherein the one or more different cancer treatment modalities comprise surgery, radiation therapy, chemotherapy, or immunotherapy.
(Item 194)
194. The method of any one of items 152-193, wherein the therapeutically effective dose is about 1, 3, or 10 mg/kg.
(Item 195)
194. The method of any one of items 152-193, wherein the therapeutically effective dose is a flat dose of between about 100-1500 mg.
(Item 196)
196. The method of claim 195, wherein the therapeutically effective dose is about a 100 mg flat dose; about a 200 mg flat dose; about a 300 mg flat dose; about a 400 mg flat dose; about a 500 mg flat dose; about a 600 mg flat dose; about a 700 mg flat dose; about a 800 mg flat dose; about a 900 mg flat dose; about a 1000 mg flat dose; about a 1100 mg flat dose; about a 1200 mg flat dose; about a 1300 mg flat dose; about a 1400 mg flat dose; or about a 1500 mg flat dose.
(Item 197)
196. The method of claim 195, wherein the therapeutically effective dose is a flat dose of between about 100 mg and 500 mg.
(Item 198)
196. The method of claim 195, wherein the therapeutically effective dose is a flat dose of between about 1000-1500 mg.
(Item 199)
196. The method of claim 195, wherein the therapeutically effective dose is a flat dose of about 100 mg.
(Item 200)
196. The method of claim 195, wherein the therapeutically effective dose is a flat dose of about 200 mg.
(Item 201)
196. The method of claim 195, wherein the therapeutically effective dose is a flat dose of about 300 mg.
(Item 202)
196. The method of claim 195, wherein the therapeutically effective dose is a flat dose of about 500 mg.
(Item 203)
196. The method of claim 195, wherein the therapeutically effective dose is a flat dose of about 900 mg.
(Item 204)
205. The method of claim 195, wherein the therapeutically effective dose is a flat dose of about 1000 mg.
206. The method of claim 195, wherein the therapeutically effective dose is a flat dose of about 1100 mg.
207. The method of claim 195, wherein the therapeutically effective dose is a flat dose of about 1200 mg.
208. The method of claim 195, wherein the therapeutically effective dose is a flat dose of about 1300 mg.
209. The method of claim 195, wherein the therapeutically effective dose is a flat dose of about 1400 mg.
210. The method of claim 195, wherein the therapeutically effective dose is a flat dose of about 1500 mg.
209. The method of any one of paragraphs 152-209, wherein the anti-TIM-3 antibody is administered at a dosing interval of once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks.
(Item 211)
211. The method of claim 210, wherein the anti-TIM-3 antibody is administered at a dosing interval of once every two weeks.
(Item 212)
211. The method of claim 210, wherein the anti-TIM-3 antibody is administered at a dosing interval of once every three weeks.
(Item 213)
213. The method of claim 212, wherein about 100 mg of the anti-TIM-3 antibody is administered.
(Item 214)
213. The method of claim 212, wherein about 300 mg of the anti-TIM-3 antibody is administered.
(Item 215)
213. The method of claim 212, wherein about 500 mg of the anti-TIM-3 antibody is administered.
(Item 216)
213. The method of claim 212, wherein about 900 mg of the anti-TIM-3 antibody is administered.
(Item 217)
217. The method of any one of paragraphs 152-216, wherein the anti-TIM-3 antibody is administered for a period of at least 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 weeks.
(Item 218)
218. The method of any one of paragraphs 152-217, wherein the anti-TIM-3 antibody is administered intravenously.
(Item 219)
219. The method of claim 218, wherein the anti-TIM-3 antibody is administered by intravenous infusion.
(Item 220)
220. The method of any one of paragraphs 152-219, wherein the anti-TIM-3 antibody is administered with an additional therapy.
(Item 221)
221. The method of claim 220, wherein the additional therapy is surgery, radiation therapy, chemotherapy, or immunotherapy.
(Item 222)
221. The method of claim 220, wherein the additional therapy is treatment with a PARP inhibitor.
(Item 223)
223. The method of claim 222, wherein the PARP inhibitor is niraparib, olaparib, rucaparib, talazoparib, or veliparib.
(Item 224)
221. The method of claim 220, wherein the additional therapy is treatment with an anti-PD-1 antibody.
(Item 225)
225. The method of claim 224, wherein the anti-PD-1 antibody is or comprises TSR-042, nivolumab, pembrolizumab, PD-1VR, or PD-1FL.
(Item 226)
226. The method of claim 224 or 225, wherein the anti-PD-1 antibody is or comprises TSR-042.
(Item 227)
227. The method of any one of claims 224 to 226, wherein the anti-PD-1 antibody comprises a heavy chain comprising SEQ ID NO: 13 and a light chain comprising SEQ ID NO: 14.
(Item 228)
228. The method of any one of claims 224 to 227, wherein the anti-PD-1 antibody is administered to the patient at a dose of between about 100-1000 mg periodically.
(Item 229)
229. The method of claim 228, wherein the anti-PD-1 antibody is administered to the patient at a dose of about 500 mg periodically.
(Item 230)
230. The method of claim 229, wherein the anti-PD-1 antibody is administered to the patient once every three weeks.
(Item 231)
231. The method of claim 229 or 230, wherein the anti-PD-1 antibody is administered for 2 to 6 cycles.
(Item 232)
232. The method of claim 231, wherein the anti-PD-1 antibody is administered for three cycles.
(Item 233)
232. The method of claim 231, wherein the anti-PD-1 antibody is administered for four cycles.
(Item 234)
232. The method of claim 231, wherein the anti-PD-1 antibody is administered for 5 cycles.
(Item 235)
229. The method of claim 228, wherein the anti-PD-1 antibody is administered to the patient at a dose of about 1000 mg periodically.
(Item 236)
236. The method of claim 235, wherein the anti-PD-1 antibody is administered to the patient one or more times every six weeks.
(Item 237)
229. The method of claim 228, wherein the anti-PD-1 antibody is administered at a first dose of about 500 mg once every 3 weeks for 3, 4, or 5 cycles, followed by a second dose of about 1000 mg once or more every 6 weeks.
(Item 238)
238. The method of claim 237, wherein the anti-PD-1 antibody is administered at a first dose of about 500 mg once every 3 weeks for 3 cycles, followed by a second dose of about 1000 mg once or more every 6 weeks.
(Item 239)
238. The method of claim 237, wherein the anti-PD-1 antibody is administered at a first dose of about 500 mg once every three weeks for four cycles, followed by a second dose of about 1000 mg once or more every six weeks.
(Item 240)
238. The method of claim 237, wherein the anti-PD-1 antibody is administered at a first dose of about 500 mg once every three weeks for five cycles, followed by a second dose of about 1000 mg once or more every six weeks.
(Item 241)
241. The method of any one of items 237-240, wherein said second dose of 1000 mg is administered once every 6 weeks.
(Item 242)
242. The method of any one of paragraphs 237-241, wherein the therapeutically effective dose of the anti-TIM-3 antibody is a flat dose of about 100 mg.
(Item 243)
242. The method of any one of paragraphs 237-241, wherein the therapeutically effective dose of the anti-TIM-3 antibody is a flat dose of about 300 mg.
(Item 244)
242. The method of any one of items 237-241, wherein the therapeutically effective dose of the anti-TIM-3 antibody is a flat dose of about 500 mg.
(Item 245)
242. The method of any one of items 237-241, wherein the therapeutically effective dose of the anti-TIM-3 antibody is a flat dose of about 900 mg.
(Item 246)
246. The method of any one of paragraphs 242-245, wherein the anti-TIM-3 antibody is administered once every three weeks.

FIG. 1 shows a schematic diagram (not to scale) of enhanced immune cell activation by anti-TIM-3 and anti-PD1.

2A-2B show results from an exemplary T cell exhaustion model. (A) Target expression of PD-1 and TIM-3 in responder (pre-stimulation) and exhausted (post-stimulation) cells. (B) Quantification of IFNγ production in exhausted (post-stimulation) cells treated with a combination of anti-PD-1 and anti-TIM-3 antibody agents, an anti-PD-1 antibody agent, an anti-TIM-3 antibody agent, and an isotype control.

3 shows results from an in vivo efficacy study of an exemplary anti-PD-1 antibody (TSR-042) in combination with an exemplary TIM-3 antibody (TSR-022), in which huNOG-EXL mice neonatally engrafted with CD34+ hematopoietic stem cells were engrafted with A549 NSCLC cells and treated with single agents as well as a combination of anti-PD-1 and anti-TIM-3 antibodies.

FIG. 4A relates to a dose escalation study of an exemplary anti-TIM-3 antibody (TSR-022) as monotherapy or in combination with an anti-PD-1 antibody.

Figure 4B relates to an expansion cohort to evaluate the anti-tumor activity of an exemplary anti-TIM-3 antibody (TSR-022) as monotherapy or in combination with an anti-PD-1 antibody in patients with specific tumor types.

FIG. 5 describes the patient demographics and baseline characteristics of participants in the dose escalation study.

FIG. 6A shows the mean PK profile following the first dose of an exemplary anti-TIM-3 antibody (TSR-022).

Figure 6B shows TIM-3 occupancy on circulating monocytes measured by flow cytometry from whole blood samples from patients treated with an exemplary anti-TIM-3 antibody (TSR-022).

7A-7C show TIM-3 receptor occupancy for an exemplary anti-TIM-3 antibody (TSR-022) at doses of 1 mg/kg (FIG. 7A), 3 mg/kg (FIG. 7B), and 10 mg/kg (FIG. 7C), respectively, administered once every two weeks (Q2W).

8 shows the effect of treatment with an exemplary anti-TIM-3 antibody (TSR-022). Treatment durations associated with specific dosages are shown, with partial responses indicated by filled squares and stable disease indicated by filled triangles.

FIG. 9 shows a brain scan in a patient with leiomyosarcoma metastasis to the lungs and kidneys who received three doses of 10 mg/kg of an exemplary anti-TIM-3 antibody (TSR-022) prior to restaging imaging.

FIG. 10 shows a receptor occupancy study of an exemplary anti-TIM-3 antibody (TSR-022) at a flat dose of 100 mg administered once every three weeks (Q3W).

11 shows a receptor occupancy study of a flat dose of 300 mg of an exemplary anti-TIM-3 antibody (TSR-022) administered in combination with a flat dose of 500 mg of an exemplary anti-PD-1 antibody (TSR-042). A second dose of TSR-022 was administered on day 22 and RO samples were collected prior to the second dose.

Figure 12 combines mean receptor occupancy data for an exemplary anti-TIM-3 antibody (TSR-022) at doses of 1 mg/kg, 3 mg/kg, 10 mg/kg, and flat doses of 100 mg, 300 mg, and 1200 mg. The figure shows measured occupancy (free TIM-3:total TIM-3) over a range of days.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS Definitions "About": The term "about" when used herein in reference to a value refers to a value that is similar in context to the referenced value. Generally, a person of ordinary skill in the art familiar with the context will understand the appropriate degree of variation that "about" encompasses in that context. For example, in some embodiments, the term "about" can encompass a range of values within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction relative to the referenced value.

Administration: As used herein, the term "administration" typically refers to administering a composition to a subject or system to effect delivery of the composition or of an agent contained therein. Those of skill in the art will recognize the various routes that may be utilized for administration to a subject, e.g., a human, in appropriate circumstances. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. For example, in some embodiments, administration may be intraocular, oral, parenteral, topical, etc. In embodiments, administration is parenteral (e.g., intravenous administration). In embodiments, intravenous administration is intravenous infusion. In certain embodiments, administration may be bronchial (e.g., bronchial infusion), buccal, dermal (e.g., one or more of topical to the dermis, intradermal, interdermal, transdermal, etc.), enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, intraspecific organ (e.g., intrahepatic), mucosal, intranasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., intratracheal infusion), vaginal, vitreous, etc. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., multiple doses separated by time) and/or periodic (e.g., individual doses separated by a common time period) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time.

Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may include the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent such as benzyl alcohol or methylparabens; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid (EDTA); a buffer such as acetate, citric acid, or phosphate, and an agent for adjusting tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral preparations may be sealed in glass or plastic ampoules, disposable syringes, or multiple dose vials.

For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant (e.g., a gas such as carbon dioxide) or a nebulizer.

Systemic administration may be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams, as is generally known in the art.

The compounds may also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

Affinity: As known in the art, "affinity" is a measure of how tightly a particular ligand binds to its partner. Affinity can be measured in a variety of ways. In some embodiments, affinity is measured by a quantitative assay. In some embodiments, the binding partner concentration can be fixed in excess of the ligand concentration to mimic physiological conditions. Alternatively or additionally, in some embodiments, the binding partner concentration and/or the ligand concentration can be varied. In some such embodiments, affinity can be compared to a standard under comparable conditions (e.g., concentrations).

Antibody: As used herein, the term "antibody" refers to a polypeptide that contains sufficient canonical immunoglobulin sequence elements to confer specific binding to a particular target antigen. As is known in the art, intact antibodies produced in nature are tetrameric agents of approximately 150 kD composed of two identical heavy chain polypeptides (about 50 kD each) and two identical light chain polypeptides (25 kD each) that associate with each other to form what is commonly referred to as a "Y-shaped" structure. Each heavy chain is composed of at least four domains, each about 110 amino acids long, including an amino-terminal variable (VH) domain (located at the tip of the Y structure) followed by three constant domains: CH1, CH2, and a carboxy-terminal CH3 (located at the base of the stem of the Y). A short region known as the "switch" connects the heavy chain variable and constant regions. A "hinge" connects the CH2 and CH3 domains to the rest of the antibody. Two disulfide bonds in this hinge region interconnect the two heavy chain polypeptides in an intact antibody. Each light chain is composed of two domains, an amino-terminal variable (VL) domain followed by a carboxy-terminal constant (CL) domain, which are separated from each other by another "switch". Those skilled in the art are sufficiently familiar with antibody structure and sequence elements to recognize the "variable" and "constant" regions in the provided sequences, and understand that there may be some flexibility in the definition of the "boundaries" between such domains, such that different representations of the same antibody chain sequence may, for example, exhibit such boundaries at positions that are offset by one or a few residues relative to different representations of the same antibody chain sequence. An intact antibody tetramer is composed of two heavy-light chain dimers, where the heavy and light chains are linked to each other by one disulfide bond, and two other disulfide bonds connect the heavy chain hinge regions to each other, such that the dimers are linked to each other to form a tetramer. Naturally occurring antibodies are also glycosylated, typically on the CH2 domain. Each domain in a natural antibody has a structure characterized by an "immunoglobulin fold", which is formed of two beta sheets (e.g., 3-, 4-, or 5-stranded sheets) packed against each other in a compressed antiparallel beta barrel. Each variable domain contains three hypervariable loops known as "complementarity determining regions" (CDR1, CDR2, and CDR3) and four "framework" regions (FR1, FR2, FR3, and FR4) that are somewhat invariant. When a natural antibody folds, the FR regions form beta sheets that provide a structural framework for the domain, and the CDR loop regions from both the heavy and light chains are packed together in three-dimensional space to create one hypervariable antigen-binding site located at the tip of a Y-structure. The Fc region of a naturally occurring antibody binds to elements of the complement system and also to receptors on effector cells, including, for example, effector cells that mediate cytotoxicity. As is known in the art, the affinity and/or other binding attributes of the Fc region for an Fc receptor can be modulated through glycosylation or other modifications. In some embodiments, the antibodies produced and/or utilized in accordance with the present invention include a glycosylated Fc domain, including an Fc domain with such glycosylation that has been modified or altered. For purposes of the present invention, any polypeptide or polypeptide complex that includes a full immunoglobulin domain sequence as found in a natural antibody may be referred to and/or used as an "antibody," whether such polypeptide is naturally produced (e.g., generated by an organism in response to an antigen) or produced by recombinant modification, chemical synthesis, or other artificial systems or methodologies. In some embodiments, the antibody is polyclonal, and in some embodiments, the antibody is monoclonal. In some embodiments, the antibody has one or more constant region sequences characteristic of mouse, rabbit, primate, or human antibodies. In some embodiments, the antibody sequence elements are humanized, primatized, chimerized, etc., as is known in the art. Furthermore, "antibody" as used herein can refer, in appropriate embodiments (unless otherwise specified or clear from the context), to any of the constructs or formats known or developed in the art to utilize the structural and functional features of antibodies in alternative presentations. For example, in embodiments, antibodies utilized in accordance with the present invention can include, but are not limited to, intact IgA, IgG, IgE, or IgM antibodies; bi- or multispecific antibodies (e.g., Zybodies®, etc.); antibody fragments, such as Fab fragments, Fab' fragments, F(ab')2 fragments, Fd' fragments, Fd fragments, and isolated CDRs or sets thereof; single chain Fvs; polypeptide-Fc fusions; single domain antibodies (e.g., shark single domain antibodies such as IgNAR or fragments thereof); cameloid antibodies; masked antibodies (e.g., Probodies®); Small Modular antibodies (e.g., IgG, IgE, IgM ...
The antibodies may take a format selected from ImmunoPharmaceuticals ("SMIP™"); single chain or tandem diabodies (TandAb®); VHHs; Anticalins®; Nanobodies® minibodies; BiTEs®; ankyrin repeat proteins or DARPINs®; Avimers®; DARTs; TCR-like antibodies; Adnectins®; Affilins®, Trans-bodies®; Affibodies®; TrimerX®; MicroProteins; Fynomers®, Centyrins®; and KALBITOR®. In some embodiments, the antibody may lack covalent modifications (e.g., glycan attachments) that it would have if produced naturally, hi some embodiments, the antibody may contain covalent modifications (e.g., glycan attachments), payloads (e.g., detectable moieties, therapeutic moieties, catalytic moieties, etc.), or other pendant groups (e.g., poly-ethylene glycol, etc.).

Antibodies include antibody fragments and include, but are not limited to, polyclonal, monoclonal, chimeric dAbs (domain antibodies), single chain, F _ab , F _ab' , F _(ab')2 fragments, scFv, and an F _ab expression library. Antibodies can be whole antibodies, or immunoglobulins, or antibody fragments.

Antibody Drug: As used herein, the term "antibody drug" refers to an agent that specifically binds to a particular antigen. In some embodiments, the term encompasses any polypeptide or polypeptide complex that contains sufficient immunoglobulin structural elements to confer specific binding. Exemplary antibody drugs include, but are not limited to, monoclonal or polyclonal antibodies. In some embodiments, an antibody drug can include one or more constant region sequences characteristic of mouse, rabbit, primate, or human antibodies. In some embodiments, an antibody drug can include one or more sequence elements that have been humanized, primatized, chimerized, etc., as known in the art. In many embodiments, the term "antibody drug" is used to refer to one or more of the constructs or formats known or developed in the art to utilize the structural and functional characteristics of antibodies in alternative presentations. For example, in embodiments, antibody agents utilized in accordance with the present invention include, but are not limited to, intact IgA, IgG, IgE, or IgM antibodies; bi- or multispecific antibodies (e.g., Zybodies®, etc.); antibody fragments, such as Fab fragments, Fab' fragments, F(ab')2 fragments, Fd' fragments, Fd fragments, and isolated CDRs or sets thereof; single chain Fvs; polypeptide-Fc fusions; single domain antibodies (e.g., shark single domain antibodies such as IgNAR or fragments thereof); cameloid antibodies; masked antibodies (e.g., Probodies®); Small Modular The antibodies may take a format selected from ImmunoPharmaceuticals ("SMIP™"); single chain or tandem diabodies (TandAb®); VHHs; Anticalins®; Nanobodies® minibodies; BiTEs®; ankyrin repeat proteins or DARPINs®; Avimers®; DARTs; TCR-like antibodies; Adnectins®; Affilins®, Trans-bodies®; Affibodies®; TrimerX®; MicroProteins; Fynomers®, Centyrins®; and KALBITOR®. In some embodiments, the antibody may lack covalent modifications (e.g., glycan attachments) that it would have if produced naturally. In some embodiments, the antibody may contain covalent modifications (e.g., glycan attachments), a payload (e.g., detectable moieties, therapeutic moieties, catalytic moieties, etc.), or other pendant groups (e.g., poly-ethylene glycol, etc.). In many embodiments, the antibody drug is or comprises a polypeptide having an amino acid sequence that includes one or more structural elements recognized by those skilled in the art as complementarity determining regions (CDRs). In some embodiments, the antibody drug is or comprises a polypeptide having an amino acid sequence that includes at least one CDR (e.g., at least one heavy chain CDR and/or at least one light chain CDR) that is substantially identical to a CDR found in a reference antibody. In some embodiments, the included CDRs are substantially identical to the reference CDRs because they are identical in sequence or contain between 1-5 amino acid substitutions compared to the reference CDR. In some embodiments, the included CDR is substantially identical to the reference CDR by exhibiting at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the reference CDR. In some embodiments, the included CDR is substantially identical to the reference CDR by exhibiting at least 96%, 96%, 97%, 98%, 99%, or 100% sequence identity to the reference CDR. In some embodiments, the included CDR is substantially identical to the reference CDR by having at least one amino acid deleted, added, or substituted in the included CDR compared to the reference CDR, but the included CDR otherwise has an amino acid sequence identical to the amino acid sequence of the reference CDR. In some embodiments, the included CDR is substantially identical to the reference CDR by having one to five amino acids deleted, added, or substituted in the included CDR compared to the reference CDR, but the included CDR otherwise has the same amino acid sequence as the reference CDR. In some embodiments, the included CDR is substantially identical to the reference CDR by having at least one amino acid substituted in the included CDR compared to the reference CDR, but the included CDR otherwise has the same amino acid sequence as the reference CDR. In some embodiments, the included CDR is substantially identical to the reference CDR by having one to five amino acids deleted, added, or substituted in the included CDR compared to the reference CDR, but the included CDR otherwise has the same amino acid sequence as the reference CDR. In some embodiments, the antibody drug is or comprises a polypeptide having an amino acid sequence that includes structural elements recognized by those skilled in the art as an immunoglobulin variable domain. In some embodiments, the antibody drug is a polypeptide protein having a binding domain that is homologous or largely homologous to an immunoglobulin binding domain.

Binding: As used herein, the term "binding" will be understood to typically refer to a non-covalent association between or among two or more entities. "Direct" binding involves physical contact between the entities or moieties, and indirect binding involves physical interaction through physical contact with one or more intermediate entities. Binding between two or more entities can typically be assessed in any of a variety of contexts, including when the interacting entities or moieties are studied in isolation or in the context of a more complex system (e.g., covalently or otherwise associated with a carrier entity and/or in a biological system or cell). In some embodiments, "binding" refers to the type of non-covalent interaction that occurs between an immunoglobulin molecule and an antigen for which the immunoglobulin is specific. The strength, or affinity, of an immunological binding interaction can be expressed in terms of the dissociation constant ( _Kd ) of the interaction, with a smaller _Kd representing a greater affinity. The immunological binding properties of selected polypeptides can be quantified using methods well known in the art. One such method involves measuring the rates of formation and dissociation of antigen-binding site/antigen complexes, which depend on the concentrations of the complex partners, the affinity of the interaction, and geometric parameters that affect rates equally in both directions. Thus, both the "on-rate constant" (K _on ) and the "off-rate constant" (K _off ) can be determined by calculation of the concentrations and actual rates of association and dissociation. (See Nature 361:186-87 (1993)). The ratio K _off /K _on allows for the removal of all parameters not related to affinity, and is equal to the dissociation constant, K _d . (See generally, Davies et al. (1990) Annual Rev Biochem 59:439-473.)

Binding Agent: In general, the term "binding agent" is used herein to refer to any entity that binds to a target of interest as described herein. In many embodiments, a binding agent of interest is a binding agent that specifically binds to a target in that it distinguishes that target from other potential binding partners in the context of a particular interaction. In general, a binding agent can be or include an entity of any chemical class (e.g., polymeric, non-polymeric, small molecule, polypeptide, carbohydrate, lipid, nucleic acid, etc.). In some embodiments, a binding agent is a single chemical entity. In some embodiments, a binding agent is a complex of two or more separate chemical entities that associate with each other under appropriate conditions by non-covalent interactions. For example, one of skill in the art will appreciate that in some embodiments, a binding agent can include a "generic" binding moiety (e.g., biotin/avidin/streptavidin and/or a class-specific antibody) and a "specific" binding moiety (e.g., an antibody or aptamer with a specific molecular target) that is linked to the generic binding moiety partner. In some embodiments, such an approach can allow for modular assembly of multiple binding agents through linkage of different specific binding moieties to the same generic binding moiety partner. In some embodiments, the binding agent is or comprises a polypeptide (e.g., including an antibody or antibody fragment). In some embodiments, the binding agent is or comprises a small molecule. In some embodiments, the binding agent is or comprises a nucleic acid. In some embodiments, the binding agent is an aptamer. In some embodiments, the binding agent is a polymer, and in some embodiments, the binding agent is not a polymer. In some embodiments, the binding agent is non-polymeric in that it lacks a polymeric portion. In some embodiments, the binding agent is or comprises a carbohydrate. In some embodiments, the binding agent is or comprises a lectin. In some embodiments, the binding agent is or comprises a peptidomimetic. In some embodiments, the binding agent is or comprises a scaffold protein. In some embodiments, the binding agent is or comprises a mimeotope. In some embodiments, the binding agent is or comprises a nucleic acid (e.g., DNA or RNA).

Cancer: The terms "cancer," "malignancy," "neoplasm," "tumor," and "carcinoma" are used herein to refer to cells that exhibit relatively abnormal, uncontrolled, and/or autonomous growth, resulting in an abnormal growth phenotype characterized by a marked loss of cell proliferation control. In some embodiments, a tumor may be or include cells that are precancerous (e.g., benign), malignant, premetastatic, metastatic, and/or nonmetastatic. The present disclosure specifically identifies certain cancers for which the teachings may be particularly suitable. In some embodiments, a suitable cancer may be characterized by a solid tumor. In some embodiments, a suitable cancer may be characterized by a hematological tumor. Generally, different types of cancers known in the art include, for example, hematopoietic cancers including leukemia, lymphomas (Hodgkin and non-Hodgkin), myeloma and myeloproliferative disorders, sarcomas, melanomas, adenomas, cancers of solid tissues, squamous cell carcinoma of the oral cavity, throat, pharynx, and lung, liver cancer, genitourinary cancers such as prostate, cervical, bladder, uterus, and endometrial cancer, as well as renal cell carcinoma, bone cancer, pancreatic cancer, skin cancer, cutaneous and intraocular melanoma, cancers of the endocrine system, thyroid cancer, parathyroid cancer, head and neck cancer, breast cancer, gastrointestinal cancer, and nervous system cancers, benign lesions such as papillomas, etc.

Carrier: As used herein, "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the composition is administered. In some exemplary embodiments, the carrier can include sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. In some embodiments, the carrier is or includes one or more solid components. In some embodiments, the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include an isotonic agent in the composition, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride. Prolonged absorption of the injectable composition can be achieved by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

Combination Therapy: As used herein, the term "combination therapy" refers to a clinical intervention in which a subject is exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents) simultaneously. In some embodiments, the two or more therapeutic regimens may be administered simultaneously. In some embodiments, the two or more therapeutic regimens may be administered sequentially (e.g., administration of a first regimen followed by administration of any dose of a second regimen). In some embodiments, the two or more therapeutic regimens are administered in an overlapping dosing regimen. In some embodiments, administration of a combination therapy may involve administration of one or more therapeutic agents or modalities to a subject receiving another agent or modality. In some embodiments, combination therapy does not necessarily require that the individual agents be administered together in a single composition (or even simultaneously). In some embodiments, the two or more therapeutic agents or modalities of the combination therapy are administered to the subject separately, e.g., in separate compositions, via separate routes of administration (e.g., one agent orally and another agent intravenously), and/or at different times. In some embodiments, two or more therapeutic agents may be administered together in a combined composition or even in a combined compound (e.g., as part of a single chemical complex or covalent entity), via the same route of administration, and/or simultaneously.

Complete Response: As used herein, "complete response" or "CR" is used to mean the disappearance of all or substantially all target lesions. In some embodiments, CR refers to about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% reduction in the sum of diameters of target lesions (i.e., loss of lesions) relative to the baseline sum of diameters. In some embodiments, CR indicates that less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of the total lesion diameter remains after treatment. Exemplary methods for assessing complete response are set forth by the RECIST guidelines. See, for example, E. A. See Eisenhauer et al., "New response evaluation criteria in solid tumors: Revised RECIST guidelines (version 1.1.)," Eur. J. of Cancer, 45:228-247 (2009).

Dosage Form or Unit Dosage Form: Those of skill in the art will appreciate that the term "dosage form" may be used to refer to a physically discrete unit of active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined amount of active agent. In some embodiments, such amount is a unit dosage (or a fraction thereof) appropriate for administration according to a dosing regimen determined to correlate with a desired or beneficial outcome when administered to an appropriate population (i.e., using a therapeutic dosing regimen). Those of skill in the art will appreciate that the total amount of therapeutic composition or agent administered to a particular subject will be determined by one or more attending physicians and may involve administration of multiple dosage forms.

Dosing regimen or regimen: Those skilled in the art will appreciate that the term "regimen" may be used to refer to a set of unit doses (typically two or more) that are administered individually to a subject, typically separated by a time period. In some embodiments, a given therapeutic agent has a recommended dosing regimen that may involve one or more doses. In some embodiments, a dosing regimen includes multiple doses, each dose separated by time from the other doses. In some embodiments, the individual doses are separated from each other by the same length of time period, and in some embodiments, a dosing regimen includes multiple doses and at least two different time periods that separate the individual doses. In some embodiments, all doses in a dosing regimen are the same unit dose amount. In some embodiments, different doses in a dosing regimen are different amounts. In some embodiments, a dosing regimen includes a first dose in a first dose amount, followed by one or more additional doses in a second dose amount that is different from the first dose amount. In some embodiments, the dosing regimen includes a first dose in a first dose fraction followed by one or more additional doses in a second dose fraction that is the same as the first dose fraction. In some embodiments, the dosing regimen correlates with a desired or beneficial outcome when administered to an appropriate population (i.e., is a therapeutic dosing regimen). In some embodiments, the regimen includes at least one dose, which includes one unit dose of a therapeutic agent (e.g., an anti-TIM-3 antibody agent). In some embodiments, the regimen includes at least one dose, which includes two or more unit doses of a therapeutic agent. For example, a 500 mg dose can be administered as a single 500 mg unit dose or as two 250 mg unit doses. In some embodiments, the regimen correlates with or results in a desired or beneficial outcome when administered to an appropriate population (i.e., is a therapeutic regimen).

Hazard ratio: As used herein, "hazard ratio" refers to the risk or likelihood of an event occurring in the treatment arm expressed as a ratio of the event occurring in the control arm. Hazard ratios can be determined by the Cox model, a regression model of survival data, which provides an estimate of the hazard ratio and its confidence interval. The hazard ratio is an estimate of the ratio of hazard rates in the treatment group versus the control group. The hazard ratio is the likelihood that the event in question will occur in the next time interval if it has not already occurred, divided by the length of that interval. Proportional hazards regression assumes that the hazard ratio is constant over time.

Homology: As used herein, the term "homology" refers to the overall relatedness between polymer molecules, e.g., between nucleic acid molecules (e.g., DNA molecules and/or RNA molecules) and/or between polypeptide molecules. In some embodiments, polymer molecules are considered to be "homologous" to one another if the sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical. In some embodiments, polymer molecules are considered to be "homologous" to one another if the sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% similar (e.g., contain residues with related chemical properties at corresponding positions). For example, as is well known to those of skill in the art, certain amino acids are typically classified as similar to one another as being "hydrophobic" or "hydrophilic" amino acids and/or having "polar" or "non-polar" side chains. When an amino acid is substituted for another amino acid of the same type, it can often be considered a "homologous" substitution.

As will be appreciated by those skilled in the art, a variety of algorithms are available that allow for sequence comparison to determine the degree of homology, including those that allow for gaps of a designated length in one sequence relative to another when considering which residues in the different sequences "correspond" to each other. Calculation of the percent homology between two nucleic acid sequences can be performed, for example, by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of the first and second nucleic acid sequences for optimal alignment, and non-corresponding sequences can be ignored for comparison purposes). In certain embodiments, the length of the aligned sequences for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or substantially 100% of the length of the reference sequence. The nucleotides at corresponding nucleotide positions are then compared. If a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, the molecules at that position are identical, and if a position in the first sequence is occupied by a nucleotide similar to the corresponding position in the second sequence, the molecules at that position are similar. The percentage of homology between two sequences is a function of the number of identical and similar positions shared by the sequences, taking into account the number of gaps and the length of each gap that need to be introduced for optimal alignment of the two sequences. Exemplary algorithms and computer programs useful for determining the percentage of homology between two nucleotide sequences include, for example, the algorithm of Meyers and Miller (CABIOS, 1989, 4:11-17), which has been incorporated into the ALIGN program (version 2.0) using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. Alternatively, the percent homology between two nucleotide sequences can be determined using the GAP program in the GCG software package using the NWSgapdna CMP matrix.

_KD: As used herein, refers to the dissociation constant of a binding agent (e.g., an antibody or binding component thereof) from a complex with its partner (e.g., the epitope to which the antibody or binding component thereof binds).

_Koff: as used herein refers to the off rate constant for dissociation of a binding agent (e.g., an antibody or binding component thereof) from a complex with its partner (e.g., the epitope to which the antibody or binding component thereof binds).

K _on: As used herein, refers to the on rate constant for a binding agent (e.g., an antibody or binding component thereof) to associate with its partner (e.g., the epitope to which the antibody or binding component thereof binds).

Patient or Subject: As used herein, a "patient" or "subject" refers to any organism to which the indicated compound(s) described herein are administered in accordance with the present invention, for example, for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Exemplary subjects include animals. The term "animal" refers to any member of the animal kingdom. In some embodiments, "animal" refers to humans at any stage of development. In some embodiments, "animal" refers to non-human animals at any stage of development. In certain embodiments, the non-human animals are mammals (e.g., rodents, mice, rats, rabbits, monkeys, dogs, cats, sheep, cows, primates, and/or pigs). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and/or worms. In some embodiments, the animals may be transgenic animals, genetically modified animals, and/or clones. In embodiments, the animals are mammals, such as mice, rats, rabbits, non-human primates, and humans, insects, worms, etc. In preferred embodiments, the subject is a human. In some embodiments, the subject may be suffering from or susceptible to a disease, disorder, and/or condition (e.g., cancer). As used herein, a "patient population" or a "population of subjects" refers to a plurality of patients or subjects.

Partial Response: As used herein, the term "partial response" ("PR") refers to a decrease in tumor progression in a subject as indicated by a decrease in the sum of diameters of target lesions relative to the baseline sum of diameters. In some embodiments, PR refers to at least a 30% decrease in the sum of diameters of target lesions relative to the baseline sum of diameters. Exemplary methods for assessing partial response are set forth by the RECIST guidelines. See, e.g., E. A. Eisenhauer et al., "New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.)," Eur. J. of Cancer, 45:228-247 (2009).

Pharmaceutical Composition: As used herein, the term "pharmaceutical composition" refers to a composition in which an active agent (e.g., an anti-TIM-3 antibody agent and/or a PD-1 binding agent) is formulated together with one or more pharma- ceutical acceptable carriers. In some embodiments, the active agent is present in a unit dose amount appropriate for administration in a therapeutic regimen that demonstrates a statistically significant likelihood of achieving a predetermined therapeutic effect when administered to an appropriate population. In some embodiments, the pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for administration as follows: oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and targeted for systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or a sustained release formulation; topical application, e.g., as a cream, ointment, or sustained release patch or spray, e.g., applied to the skin, lungs, or mouth; vaginally or rectally, e.g., as a pessary, cream, or foam; sublingually, ocularly; transdermally; or intranasally, pulmonary, and other mucosal surfaces. In some preferred embodiments, the active agents (e.g., anti-TIM-3 antibody agents and/or PD-1 binding agents) are formulated for parenteral administration.

Pharmaceutically acceptable: As used herein, the term "pharmacologically acceptable" as applied to a carrier, diluent, or excipient used in formulating the compositions disclosed herein means that the carrier, diluent, or excipient must be compatible with the other ingredients of the composition and not deleterious to the recipient of the composition.

Progression-free survival: As used herein, the term "progression-free survival" refers to the period of time during which a subject with a disease (e.g., cancer) survives without significant worsening of the disease state. Progression-free survival may be assessed as the period of time during which there is no progression of tumor growth and/or the patient's disease state is not determined as progressive disease. In some embodiments, progression-free survival of a subject with cancer is assessed by assessing tumor (lesion) size, tumor (lesion) number, and/or metastasis.

Progression or Progressive Disease: The term "progression" or "progressive disease" ("PD") of "tumor growth" as used herein with respect to a cancer condition refers to an increase in the sum of diameters of target lesions (tumors). In some embodiments, tumor growth progression refers to at least a 20% increase in the sum of diameters of target lesions relative to the minimum sum on study (including the baseline sum if the baseline sum is the minimum on study). In some embodiments, the sum of diameters of target lesions must show an absolute increase of at least 5 mm in addition to a relative increase of 20%. The appearance of one or more new lesions may also be taken into account in determining tumor growth progression. Progression for purposes of determining progression-free survival may also be determined by meeting at least one of the following criteria: 1) Tumor assessment by CT/MRI shows progressive disease according to RECIST 1.1 or irRECIST criteria; or 2) additional diagnostic tests (e.g., histology/cytology, ultrasound techniques, endoscopy, positron emission tomography) identify new lesions or existing lesions are characterized as overt progressive disease and progressive disease according to the Gynecologic Cancer Intergroup (GCIG) criteria (Rustin et al., Int J Gynecol Cancer 2013, 133:1311-1323). 2011;21:419-423 (herein incorporated by reference in its entirety); 3) definitive clinical signs and symptoms of PD unrelated to non-malignant or iatrogenic causes ([i] refractory cancer-related pain; [ii] worsening malignant bowel obstruction/function; or [iii] overt symptomatic worsening of ascites or pleural effusion) and progression of CA-125 according to GCIG criteria.

Solid Tumor: As used herein, the term "solid tumor" refers to an abnormal mass of tissue that does not usually contain cysts or liquid areas. In some embodiments, solid tumors can be benign, and in some embodiments, solid tumors can be malignant. One of skill in the art will appreciate that different types of solid tumors are typically named for the cell type that forms them. Examples of solid tumors include carcinoma, lymphoma, and sarcoma. In some embodiments, a solid tumor can be or include a tumor of the adrenal gland, bile duct, bladder, bone, brain, breast, cervix, colon, endometrium, esophagus, eye, gallbladder, gastrointestinal tract, kidney, pharynx, liver, lung, nasal cavity, nasopharynx, oral cavity, ovary, penis, pituitary gland, prostate, retina, salivary gland, skin, small intestine, stomach, testes, thymus, thyroid, uterus, vagina, and/or vulva.

Stabilization or stable disease: As used herein, "stabilization" or "stable disease" ("SD") of tumor growth refers to neither a sufficient reduction to qualify for PR nor a sufficient increase to qualify for PD. In some embodiments, stabilization refers to a change (increase or decrease) of less than 30%, 25%, 20%, 15%, 10%, or 5% in the sum of diameters of target lesions relative to the baseline sum of diameters. Exemplary methods for assessing stabilization or stable disease of tumor growth are set forth by the RECIST guidelines. See, for example, E. A. Eisenhauer et al., "New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1.)," Eur. J. of Cancer, 45:228-247 (2009).

Therapeutically effective amount: As used herein, refers to an amount that produces a desired effect in a subject to which it is administered. In some embodiments, the term refers to an amount that is sufficient to treat a disease, disorder, and/or condition when administered to a population suffering from or susceptible to the disease, disorder, and/or condition. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence and/or severity of, and/or delays the onset of, one or more symptoms of a disease, disorder, and/or condition. Those skilled in the art will appreciate that the term "therapeutically effective amount" does not in fact require the achievement of successful treatment in a particular individual. Instead, a therapeutically effective amount is considered to be an amount that, when administered to a patient in need of such treatment, produces a particular desired pharmacological response in a meaningful number of subjects. In some embodiments, reference to a therapeutically effective amount may be a reference to the amount as measured in one or more particular tissues (e.g., tissues affected by a disease, disorder, or condition) or bodily fluids (e.g., blood, saliva, serum, sweat, tears, urine, etc.). One of ordinary skill in the art will appreciate that in some embodiments, a therapeutically effective amount of a particular agent or therapy may be formulated and/or administered in a single dose. In some embodiments, a therapeutically effective agent may be formulated and/or administered in multiple doses, e.g., as part of a dosing regimen.

Treatment: As used herein, the term "treatment" (and "treat" or "treating") refers to any administration that partially or completely relieves, ameliorates, alleviates, inhibits, delays the onset of, reduces the severity of, and/or reduces the incidence of one or more symptoms, characteristics, and/or causes of a particular disease, disorder, and/or condition. In some embodiments, such treatment may be of subjects who do not show signs of the relevant disease, disorder, and/or condition, and/or of subjects who show only early signs of the disease, disorder, and/or condition. Alternatively or additionally, such treatment may be of subjects who show one or more established signs of the relevant disease, disorder, and/or condition. In some embodiments, treatment may be of subjects who have been diagnosed as suffering from the relevant disease, disorder, and/or condition. In some embodiments, treatment may be of subjects who are known to have one or more susceptibility factors that are statistically correlated with an increased risk of developing the relevant disease, disorder, and/or condition.
Methods of treatment (including methods of cancer treatment)

Described herein are methods of treating a disorder in a subject (e.g., a disorder that would benefit from administration of an anti-TIM-3 therapy). For example, the anti-TIM-3 therapy described herein is administered, e.g., as a monotherapy or in a combination therapy, for a period of time sufficient to achieve clinical benefit or according to a regimen determined by a physician (e.g., the anti-TIM-3 therapy is administered at a dosage and number of treatment cycles determined by a physician).

In embodiments, the methods described herein are useful for increasing T cell activation or T cell effector function in a subject.

In embodiments, the methods described herein are useful for inducing an immune response in a subject.

In embodiments, the methods described herein are useful for enhancing an immune response or increasing immune cell activity in a subject.

The methods of the invention can be used to treat any type of infectious disease (i.e., a disease or disorder caused by bacteria, viruses, fungi, or parasites). Examples of infectious diseases that can be treated by the methods of the invention include, but are not limited to, diseases caused by human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), influenza virus, dengue virus, hepatitis B virus (HBV), or hepatitis C virus (HCV). When the methods of the invention treat infectious diseases, the anti-TIM-3 antibody agent can be administered in combination with at least one antibacterial agent or at least one antiviral agent. In this regard, the antibacterial agent can be any suitable antibiotic known in the art. The antiviral agent can be any suitable type of vaccine that specifically targets a particular virus (e.g., live attenuated vaccines, subunit vaccines, recombinant vector vaccines, and small molecule antiviral therapies (e.g., viral replication inhibitors and nucleoside analogs)).

The methods of the present invention can be used to treat any type of autoimmune disease (i.e., autoimmune disease as a disease or disorder caused by an overactivity of the immune system in which the body attacks and damages its own tissues), e.g., the immune system disorders described in MacKay I. R. and Rose N. R., eds., The Journal of Clinical Oncology, 1999, 144:131-132, 2002, and 2003, supra).
Autoimmune Diseases, Fifth Edition, Academic Press, Waltham, MA (2014). Examples of autoimmune diseases that can be treated by the methods of the invention include, but are not limited to, multiple myeloma, type 1 diabetes, rheumatoid arthritis, scleroderma, Crohn's disease, psoriasis, systemic lupus erythematosus (SLE), and ulcerative colitis. When the methods of the invention treat autoimmune diseases, the anti-TIM-3 antibody agents can be used in combination with anti-inflammatory agents, including, for example, corticosteroids (e.g., prednisone and fluticasone) and nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen, and naproxen).

In embodiments, the methods described herein are useful for treating T cell dysfunction disorders (e.g., cancer).

In embodiments, the methods described herein are useful for reducing a tumor or inhibiting the growth of tumor cells in a subject.

The methods of the present invention can be used to treat any type of cancer known in the art.

In embodiments, the cancer is adenocarcinoma, adenocarcinoma of the lung, acute myeloid leukemia ("AML"), acute lymphoblastic leukemia ("ALL"), adrenocortical carcinoma, anal cancer, appendix cancer, B-cell derived leukemia, B-cell derived lymphoma, bladder cancer, brain cancer, breast cancer (e.g., triple-negative breast cancer (TNBC)), fallopian tube cancer, testicular cancer, cerebral cancer, cervical cancer, choriocarcinoma, chronic myeloid leukemia, central nervous system tumors, colon adenocarcinoma, colon cancer, colorectal cancer, diffuse intrinsic pontine glioma (DIPG), diffuse large cell lymphoma ("DLBCL"), embryonal rhabdomyosarcoma (ERMS), Endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, follicular lymphoma ("FL"), gallbladder cancer, gastric cancer, gastrointestinal cancer, glioma, head and neck cancer, blood cancer, hepatocellular carcinoma, Hodgkin's lymphoma (HL)/primary mediastinal B-cell lymphoma, kidney cancer, renal clear cell carcinoma, pharyngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, Merkel cell carcinoma, mesothelioma, monocytic leukemia, multiple myeloma, myeloma, central nervous system tumors of neuroblastic origin (e.g., neuroblastoma (NB)), non-Hodgkin's lymphoma (NHL), non-small cell lung cancer (NSCLC), oral cancer, osteosarcoma, ovarian cancer (ovarian cancer), ovarian carcinoma, pancreatic cancer, peritoneal cancer, primary peritoneal cancer, prostate cancer, recurrent or refractory classical Hodgkin's lymphoma (cHL), renal cell carcinoma, rectal cancer, salivary gland cancer (e.g., salivary gland tumors), sarcoma, skin cancer, small cell lung cancer, small intestine cancer, squamous cell carcinoma of the anogenital region (e.g., anus, penis, cervix, vagina, or vulva), squamous cell carcinoma of the esophagus, squamous cell carcinoma of the head and neck (SCHNC), squamous cell carcinoma of the lung, gastric cancer, T-cell derived leukemia, T-cell derived lymphoma, thymic carcinoma, thymoma, thyroid cancer, uveal melanoma, urothelial cell carcinoma, uterine cancer, endometrial cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or Wilms' tumor.

In other embodiments, the cancer is head and neck cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), kidney cancer, bladder cancer, melanoma, Merkel cell carcinoma (see, e.g., Bhatia et al., Curr. Oncol. BRep., 13(6):488-497 (2011)), cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, breast cancer, prostate cancer, oral adenocarcinoma, thymoma, adrenocortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendix cancer, urothelial cell carcinoma, or squamous cell carcinoma (e.g., lung; anogenital region, including the anus, penis, cervix, vagina, or vulva; or esophageal squamous cell carcinoma). In some embodiments, the cancer for treatment in the context of this disclosure is melanoma, renal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gallbladder cancer, pharyngeal cancer, liver cancer, thyroid cancer, gastric cancer, salivary gland cancer, prostate cancer, pancreatic cancer, or Merkel cell carcinoma.

In embodiments, the cancer is a lymphoma, such as Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, and polycythemia vera.

In embodiments, the cancer is squamous cell carcinoma. In embodiments, the cancer is squamous cell carcinoma of the lung. In embodiments, the cancer is squamous cell carcinoma of the esophagus. In embodiments, the cancer is squamous cell carcinoma of the anogenital region (e.g., anus, penis, cervix, vagina, or vulva). In embodiments, the cancer is head and neck squamous cell carcinoma (HNSCC).

In embodiments, the cancer is bladder cancer, breast cancer (e.g., triple-negative breast cancer (TNBC)), cancer of the fallopian tubes, bile duct cancer, colon adenocarcinoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, gastric cancer, renal clear cell carcinoma, lung cancer (e.g., lung adenocarcinoma or lung squamous cell carcinoma), mesothelioma, ovarian cancer, pancreatic cancer, peritoneal cancer, prostate cancer, endometrial cancer, or uveal melanoma. In embodiments, the cancer is ovarian cancer, cancer of the fallopian tubes, or peritoneal cancer. In embodiments, the cancer is breast cancer (e.g., TNBC). In embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer). In embodiments, the cancer is prostate cancer.

In embodiments, the cancer is a cancer of the central nervous system or brain, such as neuroblastoma (NB), glioma, diffuse intrinsic pontine glioma (DIPG), pilocytic astrocytoma astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, medulloblastoma, craniopharyngioma, ventriculoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, vestibular schwannoma, adenoma, metastatic brain tumor, meningioma, spinal tumor, or medulloblastoma. In embodiments, the cancer is a central nervous system tumor.

In other embodiments, the cancer is melanoma, renal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gallbladder cancer, pharyngeal cancer, liver cancer, thyroid cancer, gastric cancer, salivary gland cancer, prostate cancer, pancreatic cancer, or Merkel cell carcinoma (see, e.g., Bhatia et al., Curr. Oncol. Rep., 13(6):488-497 (2011)).

In some embodiments, the patient or patient population has a hematological cancer. In some embodiments, the patient has a hematological cancer, such as diffuse large B-cell lymphoma ("DLBCL"), Hodgkin's lymphoma ("HL"), non-Hodgkin's lymphoma ("NHL"), follicular lymphoma ("FL"), acute myeloid leukemia ("AML"), acute lymphoblastic leukemia ("ALL"), or multiple myeloma ("MM"). In embodiments, the cancer is a blood-borne cancer, such as acute lymphoblastic leukemia ("ALL"), acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia ("AML"), acute lymphoblastic leukemia ("ALL"), acute promyelocytic leukemia ("APL"), acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute anaplastic leukemia, chronic myelocytic leukemia ("CML"), chronic lymphocytic leukemia ("CLL"), hairy cell leukemia, and multiple myeloma, acute and chronic leukemias, such as lymphoblastic, myeloid, lymphocytic, and myelocytic leukemia.

In some embodiments, the patient or patient population has a solid tumor. In embodiments, the cancer is a solid tumor, e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelioma, lymphangiosarcoma, lymphangioendothelioma, synovium, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, osteosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, squamous cell carcinoma. , basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic lung carcinoma, renal cell carcinoma, hepatoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, bladder cancer, lung cancer, epithelial carcinoma, skin cancer, melanoma, neuroblastoma (NB), or retinoblastoma. In some embodiments, the tumor is an advanced stage solid tumor. In some embodiments, the tumor is a metastatic solid tumor. In some embodiments, the patient has an MSI-H solid tumor.

In some embodiments, the patient or patient population treated by the methods of the invention has or is susceptible to cancer such as head and neck cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), kidney cancer, bladder cancer, melanoma, Merkel cell carcinoma, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, breast cancer, prostate cancer, oral adenocarcinoma, thymoma, adrenal cortical carcinoma, esophageal cancer, gastric cancer, colorectal cancer, appendix cancer, urothelial cell carcinoma, or squamous cell carcinoma (e.g., lung; anogenital area, including anus, penis, cervix, vagina, or vulva; or esophageal squamous cell carcinoma). In some embodiments, the patient or patient population treated by the methods of the invention has or is susceptible to lung cancer (e.g., NSCLC), kidney cancer, melanoma, cervical cancer, colorectal cancer, or endometrial cancer (e.g., MSS endometrial cancer or MSI-H endometrial cancer).

In some embodiments, the patient or patient population treated by the methods of the invention has or is susceptible to non-small cell lung cancer (NSCLC), hepatocellular carcinoma, renal cancer, melanoma, cervical cancer, colorectal cancer, squamous cell carcinoma of the anogenital tract (e.g., squamous cell carcinoma of the anus, penis, cervix, vagina, or vulva), head and neck cancer, triple-negative breast cancer, ovarian cancer, or endometrial cancer. In some embodiments, the patient has an advanced stage solid tumor, e.g., non-small cell lung cancer (NSCLC), hepatocellular carcinoma, renal cancer, melanoma, cervical cancer, colorectal cancer, squamous cell carcinoma of the anogenital tract (e.g., squamous cell carcinoma of the anus, penis, cervix, vagina, or vulva), head and neck cancer, triple-negative breast cancer, ovarian cancer, or endometrial cancer. In some embodiments, the patient has an advanced stage solid tumor with microsatellite instability.

In some embodiments, the cancer is a gynecological cancer (i.e., a cancer of the female reproductive system, such as ovarian cancer, fallopian tube cancer, cervical cancer, vaginal cancer, vulvar cancer, uterine cancer, or primary peritoneal cancer, or breast cancer). In some embodiments, cancers of the female reproductive system include, but are not limited to, ovarian cancer, fallopian tube cancer, peritoneal cancer, and breast cancer.

In embodiments, the cancer is ovarian cancer (e.g., serous or clear cell ovarian cancer). In embodiments, the cancer is fallopian tube cancer (e.g., serous or clear cell fallopian tube cancer). In embodiments, the cancer is primary peritoneal cancer (e.g., serous or clear cell primary peritoneal cancer).

In some embodiments, the ovarian cancer is an epithelial cancer. Epithelial cancer accounts for 85% or 90% of ovarian cancers. Historically, it was thought to start on the surface of the ovaries, but new evidence suggests that at least some ovarian cancers start in specialized cells that are part of the fallopian tubes. The fallopian tubes are small tubes that connect to a woman's ovaries, part of the female reproductive system. In a normal female reproductive system, there are two fallopian tubes, one on each side of the uterus. Cancer cells that start in the fallopian tubes can migrate to the surface of the ovaries at an early stage. The term "ovarian cancer" is often used to describe epithelial cancers that start in the ovaries, in the fallopian tubes, and in the lining of the abdominal cavity called the peritoneum. In some embodiments, the cancer is or includes a germ cell tumor. A germ cell tumor is a type of ovarian cancer that develops in the egg-producing cells of the ovaries. In some embodiments, the cancer is or includes a stromal tumor. Stromal tumors arise in the connective tissue cells that hold the ovaries together, and this connective tissue may be tissue that makes the female hormone called estrogen. In some embodiments, the cancer is or includes a granulosa cell tumor. Granulosa cell tumors secrete estrogen, which may result in abnormal vaginal bleeding at the time of diagnosis. In some embodiments, the gynecologic cancer is associated with homologous recombination deficiency/homology deficiency ("HRD") and/or BRCA1/2 mutations. In some embodiments, the gynecologic cancer is platinum sensitive. In some embodiments, the gynecologic cancer has responded to a platinum-based therapy. In some embodiments, the gynecologic cancer has developed resistance to a platinum-based therapy. In some embodiments, the gynecologic cancer has at one time shown a partial or complete response to a platinum-based therapy (e.g., a partial or complete response to the last or penultimate platinum-based therapy). In some embodiments, the gynecologic cancer is currently resistant to a platinum-based therapy.

In an embodiment, the cancer is breast cancer. Breast cancer usually begins either in the milk-producing gland cells known as lobules or in the ducts. Less commonly, breast cancer may arise in stromal tissue. Such tissues include the fat and fibrous connective tissue of the breast. Over time, breast cancer cells may invade nearby tissues such as lymph nodes under the arm or the lungs in a process known as metastasis. The stage of the breast cancer, the size of the tumor, and its rate of growth are all factors that determine the type of treatment proposed. Treatment options include surgery to remove the tumor, drug treatments including chemotherapy and hormonal therapy, radiation therapy, and immunotherapy. Prognosis and survival vary widely, with five-year relative survival rates ranging from 98% to 23%, depending on the type of breast cancer occurring. Breast cancer is the second most common cancer in the world, with approximately 1.7 million new cases in 2012, and is the fifth most common cause of cancer death, with approximately 521,000 deaths. Of these cases, approximately 15% are triple negative, meaning they do not express estrogen receptors, progesterone receptors (PR), or HER2. In some embodiments, triple negative breast cancer (TNBC) is characterized by breast cancer cells that are negative for estrogen receptor expression (<1% of cells), negative for progesterone receptor expression (<1% of cells), and negative for HER2.

In embodiments, the cancer is ER-positive breast cancer, ER-negative breast cancer, PR-positive breast cancer, PR-negative breast cancer, HER2-positive breast cancer, HER2-negative breast cancer, BRCA1/2-positive breast cancer, BRCA1/2-negative breast cancer, or triple-negative breast cancer (TNBC). In embodiments, the cancer is triple-negative breast cancer (TNBC). In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is advanced breast cancer. In some embodiments, the cancer is stage II, stage III, or stage IV breast cancer. In some embodiments, the cancer is stage IV breast cancer. In some embodiments, the breast cancer is triple-negative breast cancer.

In some embodiments, the patient or patient population treated by the disclosed methods has or is susceptible to endometrial cancer ("EC"). Endometrial cancer is the most common cancer in the female reproductive tract, accounting for 10-20 cases per 100,000 person-years. The number of new cases of endometrial cancer (EC) per year is estimated to be approximately 325,000 worldwide. Furthermore, EC is the most commonly occurring cancer in postmenopausal women. Approximately 53% of endometrial cancer cases occur in developed countries. Approximately 55,000 cases of EC were diagnosed in the United States in 2015, but currently there are no targeted therapies approved for use in EC. There is a need for agents and regimens that improve survival for advanced and recurrent EC in the 1L and 2L settings. Approximately 10,170 deaths from EC are predicted in the United States in 2016. The most common histological form is endometrioid adenocarcinoma, representing approximately 75-80% of diagnosed cases. Other histological forms include papillary serous (<10%), clear cell 4%, mucinous 1%, squamous <1%, and mixed approximately 10%.

From a pathogenetic point of view, EC is classified into two different types, so-called types I and II. Type I tumors are low-grade estrogen-associated endometrioid carcinomas (EEC), whereas type II are non-endometrioid (NEEC) (mainly serous and clear cell) carcinomas. Recently, the World Health Organization revised the pathological classification of EC, recognizing nine different subtypes of EC, with EEC and serous carcinomas (SC) accounting for the majority of cases. EEC is an estrogen-associated cancer occurring in peri-menopausal patients, preceded by precursor lesions (endometrial hyperplasia/endometrial intraepithelial neoplasia). Microscopically, low-grade EEC (EEC 1-2) contains tubular glands somewhat resembling the proliferative endometrium, with architectural complexity of fused glandular and cribriform patterns. High-grade EEC show a solid growth pattern. In contrast, SC occurs in postmenopausal patients in the absence of estrogen hypersecretion. Microscopically, SC shows thick fibrous or edematous papillae with tumor cells with large eosinophilic cytoplasm, cellular budding, and prominent stratification of anaplastic cells. The majority of EECs are low-grade tumors (grades 1 and 2) and, if confined to the uterus, are associated with a good prognosis. Grade 3 EEC (EEC3) is an aggressive tumor with a high incidence of lymph node metastasis. SC is highly aggressive, is independent of estrogen stimulation, and occurs primarily in older women. EEC3 and SC are considered high-grade tumors. SC and EEC3 were compared using Surveillance, Epidemiology, and End Results (SEER) program data from 1988 to 2001. They accounted for 10% and 15% of ECs, respectively, but 39% and 27% of cancer deaths, respectively. Endometrial cancer can also be classified into four molecular subgroups: (1) ultramutated/POLE-mutated; (2) hypermutated MSI+ (e.g., MSI-H or MSI-L); (3) low copy number/microsatellite stable (MSS); and (4) high copy number/serous. Approximately 28% of cases are MSI-high. (Murali, Lancet Oncol. (2014)). In some embodiments, the patient has a mismatch repair deficient subset of 2L endometrial cancer. In embodiments, the endometrial cancer is metastatic endometrial cancer. In embodiments, the patient has MSS endometrial cancer. In embodiments, the patient has MSI-H endometrial cancer.

In an embodiment, the cancer is lung cancer. In an embodiment, the lung cancer is squamous cell carcinoma of the lung. In an embodiment, the lung cancer is small cell lung cancer (SCLC). In an embodiment, the lung cancer is non-small cell lung cancer (NSCLC) (e.g., squamous cell NSCLC). In an embodiment, the lung cancer is ALK translocated lung cancer (e.g., ALK translocated NSCLC). In an embodiment, the cancer is NSCLC with an identified ALK translocation. In an embodiment, the lung cancer is EGFR mutated lung cancer (e.g., EGFR mutated NSCLC). In an embodiment, the cancer is NSCLC with an identified EGFR mutation.

In embodiments, the cancer is colorectal (CRC) cancer (e.g., solid tumor). In embodiments, the colorectal cancer is advanced colorectal cancer. In embodiments, the colorectal cancer is metastatic colorectal cancer. In embodiments, the colorectal cancer is MSI-H colorectal cancer. In embodiments, the colorectal cancer is MSS colorectal cancer. In embodiments, the colorectal cancer is POLE mutant colorectal cancer. In embodiments, the colorectal cancer is POLD mutant colorectal cancer. In embodiments, the colorectal cancer is TMB high colorectal cancer.

In embodiments, the cancer is melanoma. In embodiments, the melanoma is advanced melanoma. In embodiments, the melanoma is metastatic melanoma. In embodiments, the melanoma is MSI-H melanoma. In embodiments, the melanoma is MSS melanoma. In embodiments, the melanoma is POLE mutant melanoma. In embodiments, the melanoma is POLD mutant melanoma. In embodiments, the melanoma is TMB high melanoma.

In an embodiment, the cancer is advanced cancer.

In an embodiment, the cancer is a metastatic cancer.

In embodiments, the cancer is a recurrent cancer (e.g., a recurrent gynecological cancer, e.g., recurrent epithelial ovarian cancer, recurrent fallopian tube cancer, recurrent primary peritoneal cancer, or recurrent endometrial cancer).

Cancers that may be treated using the methods described herein include cancers with high tumor mutation burden (TMC), cancers with microsatellite stability (MSS), cancers characterized by microsatellite instability, cancers with high microsatellite instability status (MSI-H), cancers with low microsatellite instability status (MSI-L), cancers with high TMB and MSI-H (e.g., cancers with high TMB and MSI-L or MSS), cancers with defective DNA mismatch repair systems, cancers with abnormalities in DNA mismatch repair genes, hypermutable cancers, homologous recombination repair deficiencies/homology repair deficiencies ("HRD"), cancers with mutations in polymerase delta (POLD), and cancers with mutations in polymerase epsilon (POLE).

In some embodiments, the tumor to be treated is characterized by microsatellite instability. In some embodiments, the tumor is characterized by microsatellite instability-high status (MSI-H). Microsatellite instability ("MSI") is or includes changes in the DNA of certain cells (e.g., tumor cells) in which the number of microsatellite repeats (short repetitive sequences of DNA) differs from the number of repeats contained in the inherited DNA. Approximately 15% of sporadic colorectal cancers (CRC) have extensive alterations in the length of microsatellite (MSI) sequences, known as microsatellite instability (MSI) (Boland and Goel, 2010). Sporadic MSI CRC tumors show unique clinicopathological features, including pseudodiploid karyotype, higher incidence in older populations and women, and a relatively good prognosis (de la Chapelle and Hampel, 2010; Popat et al., 2005). MSI is also present in other tumors, such as endometrial cancer (EC), the most common gynecological malignancy (Duggan et al., 1994). Currently, the same reference Bethesda panel, originally developed to screen for inherited genetic disorders (Lynch syndrome) (Umar et al., 2004), is being applied to MSI testing for CRC and EC. However, genes that are frequently targeted by MSI in the CRC genome are less likely to have DNA slippage events in the EC genome (Gurin et al., 1999).

Microsatellite instability results from a failure to repair replication-associated errors due to an imperfect DNA mismatch repair (MMR) system. This failure allows mismatched bases to persist throughout the genome, but especially in regions of repetitive DNA known as microsatellites, resulting in increased mutation load. It has been demonstrated that at least some tumors characterized by MSI-H have improved response to certain anti-PD-1 agents (Le et al., (2015) N. Engl. J. Med. 372(26):2509-2520; Westdorp et al. (2016) Cancer Immunol. Immunother. 65(10):1249-1259). In some embodiments, the cancer has microsatellite instability with high frequency of microsatellite instability (e.g., MSI-H status). In some embodiments, the cancer has a microsatellite instability status of low microsatellite instability (e.g., MSI-low). In some embodiments, the cancer has a microsatellite instability status of microsatellite stable (e.g., MSS status). In some embodiments, the microsatellite instability status is assessed by next generation sequencing (NGS)-based assays, immunohistochemistry (IHC)-based assays, and PCR-based assays. In some embodiments, the microsatellite instability is detected by NGS. In some embodiments, the microsatellite instability is detected by IHC. In some embodiments, the microsatellite instability is detected by PCR.

In an embodiment, the patient has MSI-L cancer.

In embodiments, the patient has an MSI-H cancer. In some embodiments, the patient has an MSI-H solid tumor. In embodiments, the MSI-H cancer is an MSI-H endometrial cancer. In embodiments, the MSI-H cancer is a solid tumor. In embodiments, the MSI-H cancer is a metastatic tumor. In embodiments, the MSI-H cancer is an endometrial cancer. In embodiments, the MSI-H cancer is a non-endometrial cancer. In embodiments, the MSI-H cancer is colorectal cancer.

In an embodiment, the patient has MSS cancer. In an embodiment, the MSS cancer is MSS endometrial cancer.

In embodiments, the cancer is associated with a POLE (DNA polymerase epsilon) mutation (i.e., the cancer is a POLE mutated cancer). In embodiments, the POLE mutation is a mutation in the endonuclease domain. In some embodiments, the POLE mutation is a germline mutation. In some embodiments, the POLE mutation is a sporadic mutation. In embodiments, the MSI cancer is also associated with a POLE mutation. In embodiments, the MSS cancer is also associated with a POLE mutation. In embodiments, the POLE mutation is identified using sequencing. In embodiments, the POLE mutated cancer is endometrial cancer. In embodiments, the POLE mutated cancer is colon cancer. In embodiments, the POLE mutated cancer is pancreatic cancer, ovarian cancer, or small intestine cancer.

In embodiments, the cancer is associated with a POLD (DNA polymerase delta) mutation (i.e., the cancer is a POLD-mutated cancer). In embodiments, the POLD mutation is a mutation in the endonuclease domain. In some embodiments, the POLD mutation is a somatic mutation. In some embodiments, the POLD mutation is a germline mutation. In embodiments, the POLD-mutated cancer is identified using sequencing. In embodiments, the POLD-mutated cancer is endometrial cancer. In embodiments, the POLD-mutated cancer is colorectal cancer. In embodiments, the POLD-mutated cancer is brain cancer.

In some embodiments, the patient has a mismatch repair deficient cancer.

In an embodiment, the MMRd cancer is colorectal cancer.

Microsatellite instability can result from failure to repair replication-associated errors due to an imperfect DNA mismatch repair (MMR) system. This failure allows mismatched bases to persist throughout the genome, but especially in regions of repetitive DNA known as microsatellites, resulting in increased mutational load, which may improve response to certain anti-PD-1 drugs. Ibid. In some embodiments, MSI-H status is assessed by NGS-based assays and/or PCR-based MSI assays. In some embodiments, microsatellite instability is detected by next-generation sequencing. In embodiments, microsatellite instability is detected using immunohistochemistry (IHC) testing.

In embodiments, the cancer (e.g., an MMRd cancer) is characterized by high tumor mutation burden (i.e., the cancer is a TMB high cancer). In some embodiments, the cancer is associated with high TMB and MSI-H. In some embodiments, the cancer is associated with high TMB and MSI-L or MSS. In some embodiments, the cancer is endometrial cancer with high TMB. In some related embodiments, the endometrial cancer is associated with high TMB and MSI-H. In some related embodiments, the endometrial cancer is associated with high TMB and MSI-L or MSS. In embodiments, the TMB high cancer is colorectal cancer. In embodiments, the TMB high cancer is lung cancer (e.g., small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC), e.g., squamous NSCLC or non-squamous NSCLC). In embodiments, the TMB high cancer is melanoma. In embodiments, the TMB high cancer is urothelial cancer.

In an embodiment, the patient has a cancer with high expression of tumor infiltrating lymphocytes (TILs), i.e., the patient has a TIL high cancer. In an embodiment, the TIL high cancer is a breast cancer (e.g., triple negative breast cancer (TNBC) or HER2 positive breast cancer). In an embodiment, the TIL high cancer is a metastatic cancer (e.g., metastatic breast cancer).

In embodiments, immune-related gene expression signatures may predict response of cancer to anti-PD-1 therapy as described herein. For example, a gene panel including genes involved in IFN-γ signaling may be useful in identifying cancer patients who may benefit from anti-PD-1 therapy. Exemplary gene panels are described in Ayers et al., J. Clin. Invest., 127(8):2930-2940, 2017. In embodiments, the cancer patient has a cancer that is breast cancer (TNBC) or ovarian cancer. In embodiments, the cancer patient has a cancer that is bladder cancer, gastric cancer, cholangiocarcinoma, esophageal cancer, or head and neck squamous cell carcinoma (HNSCC). In embodiments, the cancer patient has a cancer that is anal cancer or colorectal cancer.

In some embodiments, the patient has a tumor that expresses PD-L1. In some embodiments, PD-L1 status is assessed in the patient or patient population. In some embodiments, mutational load and baseline gene expression profile in an archival or fresh pre-treatment biopsy are assessed before, during, and/or after treatment with an anti-PD-1 agent. In some embodiments, TIM-3 and/or LAG-3 status and/or expression is assessed in the patient.

In some embodiments, the patient has been previously treated with one or more different cancer treatment modalities. In some embodiments, at least a portion of the patients in the cancer patient population have been previously treated with one or more of surgery, radiation therapy, chemotherapy, or immunotherapy. In some embodiments, at least a portion of the patients in the cancer patient population have been previously treated with chemotherapy (e.g., platinum-based chemotherapy). For example, a patient who has undergone two lines of cancer treatment may be identified as a 2L cancer patient (e.g., a 2L NSCLC patient). In embodiments, the patient has undergone two or more lines of cancer treatment (e.g., a 2L+ cancer patient, e.g., a 2L+ endometrial cancer patient). In embodiments, the patient has not been previously treated with an anti-PD-1 therapy. In embodiments, the patient has undergone at least one line of cancer treatment (e.g., the patient has undergone at least one or at least two lines of cancer treatment). In embodiments, the patient has undergone at least one line of metastatic cancer treatment (e.g., the patient has undergone one or two lines of metastatic cancer treatment). In embodiments, the subject is refractory to treatment with an agent that inhibits PD-1. In embodiments, the subject is refractory to treatment with an agent that inhibits PD-1. In embodiments, the methods described herein sensitize the subject to treatment with an agent that inhibits PD-1.
T-cell immunoglobulin and mucin domain-3 (TIM-3)

The T cell and mucin domain-3 (TIM-3) protein, also known as hepatitis A virus cell receptor 2 (HAVCR2), is a Th1-specific cell surface protein that regulates macrophage activation and enhances the severity of experimental autoimmune encephalomyelitis in mice. TIM-3 is highly expressed on the surface of multiple immune cell types, including Th1 IFN-γ+ cells, Th17 cells, natural killer (NK) cells, monocytes, and tumor-associated dendritic cells (DCs) (see, e.g., Clayton et al., J. Immunol., 192(2):782-791 (2014); Jones et al., J. Exp. Med., 205:2763-2779 (2008); Monney et al., Nature, 415:536-54). 1 (2002); Hastings et al., Eur. J. Immunol., 39:2492-2501 (2009); Seki et al., Clin. Immunol., 127:78-88 (2008); Ju et al., B. J. Hepatol., 52:322-329 (2010); Anderson et al., Science, 318:1141-1143 (2007); Baitsch et al., PLoS ONE, 7:e30852 (2012); Ndhlovu et al., Blood, 119:3734-3743 (2012)). TIM-3 is also highly expressed on "exhausted" or "rogue" CD8+ T cells in various chronic viral infections (e.g., HIV, HCV, and HBV) and in certain cancers (see, e.g., McMahan et al., J. Clin. Invest., 120(12):4546-4557 (2010); Jin et al., Proc Natl Acad Sci. USA, 107(33):14733-14738(2010); Golden-Mason et al., J. Virol., 83(18):9122-9130(2009); Jones et al., supra; Fourcade et al., J. Exp. Med., 207(10):2175-2186(2010); Sakuishi et al., J. Exp. Med., 207(10):2187-2194(2010); Zhou et al., Blood, 117(17):4501-4510(2011); Ngiow et al., Cancer Res., 71(10):3540-3551(2011)).

Putative ligands for TIM-3 include phosphatidylserine (Nakayama et al., Blood, 113:3821-3830 (2009)), galectin-9 (Zhu et al., Nat. Immunol., 6:1245-1252 (2005)), high mobility group protein 1 (HMGB1) (Chiba et al., Nature Immunology, 13:832-842 (2012)), and carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) (Huang et al., Nature, 517(7534):386-90 (2015)).

TIM-3 functions to regulate various aspects of the immune response. Interaction of TIM-3 with galectin-9 (Gal-9) induces cell death, and in vivo blockade of this interaction exacerbates autoimmunity and abrogates tolerance in experimental models, strongly suggesting that TIM-3 is a negative regulatory molecule. In contrast to its effects on T cells, TIM-3-Gal-9 interaction exerts antibacterial effects by promoting macrophage clearance of intracellular pathogens (see, e.g., Sakuishi et al., Trends in Immunology, 32(8):345-349 (2011)). In vivo inhibition of TIM-3 has been shown to enhance the pathological severity of experimental autoimmune encephalomyelitis (Monney et al., supra; and Anderson, A.C. and Anderson, D.E., Curr. Opin. Immunol., 18:665-669 (2006)). Studies also suggest that dysregulation of the TIM-3-Gal-9 pathway may play a role in chronic autoimmune diseases such as multiple sclerosis (Anderson and Anderson, supra). TIM-3 promotes the clearance of apoptotic cells by binding to phosphatidylserine through its unique binding cleft (see, e.g., DeKruyff et al., J. Immunol., 184(4):1918-1930 (2010)).

Inhibition of TIM-3 activity (e.g., via the use of monoclonal antibodies) is currently being investigated as a tumor immunotherapy based on preclinical studies (see, e.g., Ngiow et al., Cancer Res., 71(21):1-5 (2011); Guo et al., Journal of Translational Medicine, 11:215 (2013); and Ngiow et al., Cancer Res., 71(21):6567-6571 (2011)).

The present disclosure provides certain antibody agents and related methods for the treatment of cancer.
Anti-TIM-3 antibody drugs

The present disclosure provides methods of treating cancer that include administering a composition that delivers a particular anti-TIM-3 antibody agent according to a regimen that can achieve clinical benefit. The present disclosure describes, at least in part, anti-TIM-3 antibody agents and various compositions and methods related thereto.

In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain having an amino acid sequence comprising SEQ ID NO:1 or SEQ ID NO:7.
SEQ ID NO:1
EVQLLESGGGLVQPGGSLRLSCAAAASGFTFSSYDMSWVRQAPGKGLDWVSTISGGGTYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASMDYWGQGTTVTVSSA
SEQ ID NO:7
EVQLLESGGGLVQPGGSLRLSCAAAASGFTFSSYDMSWVRQAPGKGLDWVSTISGGGTYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASMDYWGQGTTVTVSS

In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin light chain variable domain having an amino acid sequence comprising SEQ ID NO:2 or SEQ ID NO:8.
SEQ ID NO:2
DIQMTQSPSSLSASVGDRVTITCRASQSIRRYLNWYHQKPGKAPKLLIYGASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQSHSAPLTFGGGTKVEIKR
SEQ ID NO:8
DIQMTQSPSSLSASVGDRVTITCRASQSIRRYLNWYHQKPGKAPKLLIYGASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQSHSAPLTFGGGTKVEIK

In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain variable domain having an amino acid sequence comprising SEQ ID NO:1 or SEQ ID NO:7, and/or an immunoglobulin light chain variable domain having an amino acid sequence comprising SEQ ID NO:2 or SEQ ID NO:8.

In some embodiments, an anti-TIM-3 antibody agent comprises variable heavy chain complementarity determining regions 1, 2, and/or 3 (VH-CDRs), which comprise the amino acid sequences GFTFSSYDMS (SEQ ID NO:21), TISGGGTYTYYQDSVK (SEQ ID NO:22), and/or MDY (SEQ ID NO:23), respectively. In some embodiments, an anti-TIM-3 antibody agent comprises variable light chain complementarity determining regions 1, 2, and/or 3 (VH-CDRs), which comprise the amino acid sequences RASQSIRRYLN (SEQ ID NO:24), GASTLQS (SEQ ID NO:25), and/or QQSHSAPLT (SEQ ID NO:26), respectively. In some embodiments, an anti-TIM-3 antibody agent comprises the VH-CDR sequences of SEQ ID NOs:21, 22, and 23, and the VL-CDR sequences of SEQ ID NOs:24, 25, and 26. See Table 1.

In some embodiments, the anti-TIM-3 antibody agent is a monoclonal antibody. Particular antibodies of the invention bind to TIM-3 with high affinity and effectively neutralize TIM-3 activity. Particular antibody heavy chain polypeptide (SEQ ID NO:3) and light chain polypeptide (SEQ ID NO:4) sequences are expressly provided.
Anti-TIM-3 antibody heavy chain polypeptide (SEQ ID NO:3)
EVQLLESGGGLVQPGGSLRLSCAAAASGFTFSSYDMSWVRQAPGKGLDWVSTISGGGTYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASMDYWGQGTTVTVSSASTKGPSVFPLAPCCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPPCPAPEFLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK Anti-TIM-3 antibody light chain polypeptide (SEQ ID NO: 4)
DIQMTQSPSSLSASVGDRVTITCRASQSIRRYLNWYHQKPGKAPKLLIYGASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQSHSAPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

The present disclosure provides an isolated immunoglobulin heavy chain polypeptide having an amino acid sequence set forth in SEQ ID NO:3. Additionally, the present disclosure provides an immunoglobulin heavy chain polypeptide having an amino acid sequence sharing at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to the amino acid sequence set forth in SEQ ID NO:3. In some embodiments, the sequence differences relative to the sequence set forth in SEQ ID NO:3 are not within the CDRs. In some embodiments, the isolated immunoglobulin heavy chain polypeptide comprises all three CDRs of SEQ ID NO:3. In some embodiments, the immunoglobulin heavy chain polypeptide comprises a signal peptide. In some embodiments, the immunoglobulin heavy chain polypeptide comprising a signal peptide has the amino acid sequence set forth in SEQ ID NO:5.
Anti-TIM-3 antibody heavy chain polypeptide with signal sequence (SEQ ID NO:5)
MEFGLSWLFLVAILKGVQCEVQLLESGGGLVQPGGSLRLSCAAAASGFTFSSYDMSWVRQAPGKGLDWVSTISGGGTYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASMDYWGQGTTVTVSSASTKGPSVFPLAPCCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

In some embodiments, the provided immunoglobulin heavy chain polypeptide is or comprises an IgG4 polypeptide. In some embodiments, the provided immunoglobulin heavy chain polypeptide comprises a human IGHG4*01 polypeptide. In some embodiments, the provided immunoglobulin heavy chain polypeptide comprises one or more mutations in an IgG heavy chain region. In some embodiments, the provided immunoglobulin heavy chain polypeptide comprises an IgG4 heavy chain constant region having one or more mutations in the heavy chain constant region. In some embodiments, the provided immunoglobulin heavy chain polypeptide comprises an IgG4 heavy chain constant region having one or more mutations in the hinge region. In some embodiments, it is contemplated that the mutation in the IgG4 hinge region may prevent half molecule exchange with other IgG4 molecules. In some embodiments, the one or more mutations in the hinge region of IgG4 may comprise a stabilizing serine to proline mutation that prevents half molecule exchange with other IgG4 molecules. In some embodiments, the one or more mutations in the hinge region of IgG4 can include an S228P mutation. See, e.g., J. Biol. Chem. 2015;290(9):5462-5469.

The present disclosure provides an isolated immunoglobulin light chain polypeptide having an amino acid sequence set forth in SEQ ID NO:4. Additionally, the present disclosure provides an immunoglobulin light chain polypeptide having an amino acid sequence that shares at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity with the amino acid sequence set forth in SEQ ID NO:4. In some embodiments, the sequence differences relative to the sequence set forth in SEQ ID NO:4 are not within the CDRs. In some embodiments, the isolated immunoglobulin light chain polypeptide comprises all three CDRs of SEQ ID NO:4. In some embodiments, the provided immunoglobulin light chain polypeptide is a kappa light chain. In some embodiments, the provided immunoglobulin light chain polypeptide comprises a human IGKC*01 polypeptide. In some embodiments, the immunoglobulin light chain polypeptide comprises a signal peptide. In some embodiments, the immunoglobulin light chain polypeptide comprising a signal peptide has the amino acid sequence set forth in SEQ ID NO:6.
Anti-TIM-3 antibody light chain polypeptide with signal sequence (SEQ ID NO:6)
MDMRVPAQLLGLLLLWLRGARC DIQMTQSPSSLSASVGDRVTITCRASQSIRRYLNWYHQKPGKAPKLLIYGASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQSHSAPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

In some embodiments, the disclosure provides an anti-TIM-3 antibody agent comprising at least one immunoglobulin heavy chain having the amino acid sequence set forth in SEQ ID NO:3 and at least one immunoglobulin light chain having the amino acid sequence set forth in SEQ ID NO:4. In some embodiments, the anti-TIM-3 antibody agent comprises two immunoglobulin heavy chains, each having the amino acid sequence set forth in SEQ ID NO:3. Alternatively or additionally, in some embodiments, the anti-TIM-3 antibody agent comprises two immunoglobulin light chains, each having the amino acid sequence set forth in SEQ ID NO:4. In some embodiments, the anti-TIM-3 antibody agent has a canonical antibody format.

In some embodiments, the provided heavy chains, light chains, and/or antibody agents are glycosylated at one or more sites. In some embodiments, the glycans are N-linked to the Fc region. In some embodiments, the antibody agents are glycosylated at Asn297 (Kabat numbering). In some embodiments, the disclosure provides compositions that include heavy chains, light chains, and/or antibody agents in one or more glycoforms as described herein. In some embodiments, the provided compositions include multiple such glycoforms present in specified absolute and/or relative amounts. In some embodiments, the disclosure provides compositions that may be substantially free of heavy chains, light chains, and/or antibody agents in one or more specific glycoforms as described herein.

In embodiments, the TIM-3 binding agent is an anti-TIM-3 antibody that is TSR-022, which comprises a humanized monoclonal anti-TIM-3 antibody comprising a heavy chain having an amino acid sequence comprising SEQ ID NO:3 and a light chain having an amino acid sequence comprising SEQ ID NO:4. This anti-TIM-3 antibody utilizes the human IGHG4*01 heavy chain gene and the human IGKC*01 light chain gene as a scaffold. Additionally, there is a single Ser to Pro point mutation at canonical position S228 in the hinge region of the IgG4 heavy chain, which corresponds to residue 240 of SEQ ID NO:5, which contains the signal sequence. Without wishing to be bound by theory, it is hypothesized that this point mutation acts to stabilize the antibody heavy chain hinge.

Further biophysical and biochemical characterization of this exemplary monoclonal anti-TIM-3 antibody is provided with respect to the observed disulfide linkages and glycosylation. Lys-C and tryptic peptides were well separated and detected by online LC-MS analysis. Disulfide bond linkages were confirmed by comparison of total ion chromatograms from non-reducing (NR) and reducing conditions. Disulfide linkages are consistent with the predicted disulfide linkage pattern in the IgG4 molecule. Residues involved in predicted inter- and intra-chain disulfide linkages are tabulated below (Tables 2, 3, and 4).

This exemplary anti-TIM-3 antibody exhibits an occupied N-glycosylation site at asparagine residue 290 within the CH2 domain of each heavy chain in the mature protein sequence (SEQ ID NO:1). The expressed N-glycosylation at this site is a mixture of oligosaccharide species typically observed on IgG expressed in mammalian cell culture; for example, shown below are the relative abundances of glycan species from a preparation of this exemplary anti-TIM-3 antibody cultured in Chinese hamster ovary (CHO) cells (Table 5).

PD-1 binding agents

The present disclosure provides methods of treating cancer, further comprising administering a composition that delivers a particular programmed death protein 1 (PD-1) binding agent according to a regimen that can achieve clinical benefit. The present disclosure describes, at least in part, PD-1 binding agents (e.g., anti-PD-1 antibody agents) and various compositions and methods related thereto. In some embodiments, the PD-1 binding agent is a monoclonal antibody.

In some embodiments, the PD-1-binding agent comprises an immunoglobulin heavy chain variable domain having an amino acid sequence comprising SEQ ID NO:11 or SEQ ID NO:17.
SEQ ID NO:11
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSTISGGGSYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYAMDYWGQGTTVTVSSA
SEQ ID NO:17
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSSYDMSWVRQAPGKGLEWVSTISGGGSYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYAMDYWGQGTTVTVSS

In some embodiments, the PD-1-binding agent comprises an immunoglobulin light chain variable domain having an amino acid sequence comprising SEQ ID NO:12 or SEQ ID NO:18.
SEQ ID NO:12
DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASTLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQGTKLEIKR
SEQ ID NO:18
DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASTLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQGTKLEIK

In some embodiments, the PD-1-binding agent comprises an immunoglobulin heavy chain variable domain having an amino acid sequence comprising SEQ ID NO:11 or SEQ ID NO:17, and/or an immunoglobulin light chain variable domain having an amino acid sequence comprising SEQ ID NO:12 or SEQ ID NO:18. In some embodiments, the PD-1-binding agent is or comprises an immunoglobulin G4 (IgG4) humanized monoclonal antibody (mAb). In some embodiments, the PD-1-binding agent comprises a human IGHG4*01 polypeptide. In some embodiments, the PD-1-binding agent comprises one or more mutations in an IgG heavy chain region. In some embodiments, the PD-1-binding agent comprises an IgG4 heavy chain constant region having one or more mutations in the heavy chain constant region. In some embodiments, the PD-1-binding agent comprises an IgG4 heavy chain constant region having one or more mutations in the hinge region. In some embodiments, it is contemplated that mutations in the IgG4 hinge region may prevent half molecule exchange with other IgG4 molecules. In some embodiments, the one or more mutations in the hinge region of IgG4 can include a stabilizing serine to proline mutation that prevents half-molecule exchange with other IgG4 molecules. In some embodiments, the one or more mutations in the hinge region of IgG4 can include a S228P mutation. See, e.g., J. Biol. Chem. 2015;290(9):5462-5469.

In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain polypeptide having an amino acid sequence comprising SEQ ID NO:13.
SEQ ID NO:13 - Anti-PD-1 antibody heavy chain polypeptide ( CDR sequence )
EVQLLESGGGLVQPGGSLRLSCAASGFTFS SYDMS WVRQAPGKGLEVSS TISGGGSYTYYQDSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAS PYYAMDY WGQGTTVTVSSASTKGPSVFPLAPCCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWY VDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

In some embodiments, the PD-1 binding agent comprises an immunoglobulin light chain polypeptide having an amino acid sequence comprising SEQ ID NO:14.
SEQ ID NO:14 - Anti-PD-1 antibody light chain polypeptide ( CDR sequence )
DIQLTQSPSFLSAYVGDRVTITC KASQDVGTAVA WYQQKPGKAPKLLIY WASTLHT GVPSRFSGSGSGTEFTLTISSLQPEDFATYYC QHYSSYPWT FGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

The present disclosure provides an isolated immunoglobulin heavy chain polypeptide having an amino acid sequence set forth in SEQ ID NO: 13. Additionally, the present disclosure provides an immunoglobulin heavy chain polypeptide having an amino acid sequence sharing at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to the amino acid sequence set forth in SEQ ID NO: 13. In some embodiments, the sequence differences relative to the sequence set forth in SEQ ID NO: 13 are not within the CDRs. In some embodiments, the isolated immunoglobulin heavy chain polypeptide comprises all three CDRs of SEQ ID NO: 13. In some embodiments, the immunoglobulin heavy chain polypeptide comprises a signal peptide. In some embodiments, the immunoglobulin heavy chain polypeptide comprising a signal peptide has the amino acid sequence set forth in SEQ ID NO: 15.
Anti-PD-1 antibody heavy chain polypeptide with signal sequence (SEQ ID NO: 15)
MEFGLSWLFLVAILKGVQCEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSTISGGGSYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYAMDYWGQGTTVTVSSASTKGPSVFPLAPCCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

The present disclosure provides an isolated immunoglobulin light chain polypeptide having an amino acid sequence set forth in SEQ ID NO: 14. Additionally, the present disclosure provides an immunoglobulin light chain polypeptide having an amino acid sequence that shares at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to the amino acid sequence set forth in SEQ ID NO: 14. In some embodiments, the sequence differences relative to the sequence set forth in SEQ ID NO: 14 are not within the CDRs. In some embodiments, the isolated immunoglobulin light chain polypeptide comprises all three CDRs of SEQ ID NO: 14. In some embodiments, the provided immunoglobulin light chain polypeptide is a kappa light chain. In some embodiments, the provided immunoglobulin light chain polypeptide comprises a human IGKC*01 polypeptide. In some embodiments, the immunoglobulin light chain polypeptide comprises a signal peptide. In some embodiments, the immunoglobulin light chain polypeptide comprising a signal peptide has the amino acid sequence set forth in SEQ ID NO: 16.
Anti-PD-1 antibody light chain polypeptide with signal sequence (SEQ ID NO: 16)
MDMRVPAQLLGLLLWLPGARCDIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASTLHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NOs:13 and 14 describe an exemplary humanized monoclonal anti-PD-1 antibody (TSR-042) that utilizes the human IGHG4*01 heavy chain gene and the human IGKC*01 light chain gene as a scaffold. There is a single Ser to Pro point mutation within the hinge region of the IgG4 heavy chain. This mutation is at the canonical S228 position. Without wishing to be bound by theory, it is hypothesized that this point mutation acts to stabilize the hinge of the antibody heavy chain.

Further biophysical and biochemical characterization of this exemplary humanized monoclonal anti-PD-1 antibody is provided herein, which is consistent with the predicted disulfide linkage pattern in an IgG4 molecule. Residues involved in predicted inter- and intrachain disulfide linkages are tabulated below (Tables 6 and 7).

This exemplary anti-PD-1 antibody exhibits an occupied N-glycosylation site at asparagine residue 293 within the CH2 domain of each heavy chain in the mature protein sequence (SEQ ID NO: 13). The expressed N-glycosylation at this site is a mixture of oligosaccharide species typically observed on IgG expressed in mammalian cell culture; for example, shown below are the relative abundances of glycan species from a preparation of this exemplary anti-PD-1 antibody cultured in Chinese Hamster Ovary (CHO) cells (Table 8).

In some embodiments, the disclosure provides an anti-PD-1 antibody agent comprising at least one immunoglobulin heavy chain having the amino acid sequence set forth in SEQ ID NO: 13 and at least one immunoglobulin light chain having the amino acid sequence set forth in SEQ ID NO: 14. In some embodiments, the anti-PD-1 antibody agent comprises two immunoglobulin heavy chains, each having the amino acid sequence set forth in SEQ ID NO: 13. Alternatively or additionally, in some embodiments, the anti-PD-1 antibody agent comprises two immunoglobulin light chains, each having the amino acid sequence set forth in SEQ ID NO: 14. In some embodiments, the anti-PD-1 antibody agent has a canonical antibody format.

In some embodiments, the provided heavy chains, light chains, and/or antibody agents have a structure that includes one or more disulfide bonds. In some embodiments, the one or more disulfide bonds are or include disulfide bonds at predicted positions in an IgG4 immunoglobulin.

In some embodiments, the PD-1 binding agent is glycosylated at one or more sites. As used herein, a "glycan" is a sugar polymer (moiety) component of a glycoprotein. The term "glycan" encompasses free glycans, including glycans that have been cleaved or otherwise released from a glycoprotein. In some embodiments, the disclosure provides compositions comprising one or more glycoforms of a heavy chain, light chain, and/or antibody agent as described herein. In some embodiments, the glycan is N-linked to the Fc region. In some embodiments, the PD-1 binding agent is glycosylated at Asn297 (Kabat numbering).

As used herein, the term "glycoform" refers to a particular form of a glycoprotein. That is, when a glycoprotein comprises a particular polypeptide that has the potential to be linked to different glycans or sets of glycans, each different version of the glycoprotein (i.e., when that polypeptide is linked to a particular glycan or set of glycans) is referred to as a "glycoform." In some embodiments, the compositions provided include multiple glycoforms of one or more of the heavy chains, light chains, and/or antibody agents as described herein.

In some embodiments, the antagonist activity of the PD-1 binding agent in blocking PD-1/PD-L1 or PD-L2 interactions can be confirmed or determined using flow cytometry to measure binding of labeled PD-L1 and PD-L2 expressed as mouse IgG1 fusion proteins (PD-L1 mFc or PD-L2 mFc) to PD-1 expressing cells. In some embodiments, the PD-1 binding agent can block PD-1/PD-L1 and PD-1/PD-L2 binding more efficiently than an IgG4 isotype control.

In some embodiments, the PD-1-binding agent can effectively neutralize PD-1 activity (e.g., inhibit binding of PD-1 to PD-L1 and PD-L2). In some embodiments, the functional antagonist activity of the PD-1-binding agent can be confirmed or determined in a mixed lymphocyte reaction (MLR) demonstrating enhanced interleukin (IL)-2 production upon addition of the PD-1-binding agent. In some embodiments, the MLR assay can be performed using primary human CD4+ T cells as responders and human dendritic cells as stimulators.
Expression and Formulation

In some embodiments, the anti-TIM-3 antibody agent and/or the PD-1 binding agent are expressed from a vector that includes one or more nucleic acid sequences.

In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain polypeptide encoded by a nucleotide sequence comprising SEQ ID NO:9.
Nucleotide sequence encoding anti-TIM-3 antibody heavy chain polypeptide (SEQ ID NO:9)
GAG GTG CAG CTG TTG GAG TCT GGG GGA GGC TTG GTA CAG CCT GGG GGG TCC CTG AGA CTC TCC TGT GCA GCA GCC TCT GGA TTC ACT TTC AGT AGC TAT GAC ATG TCT TGG GTC CGC CAG GCT CCA GGG AAG GGG CTG GAC TGG GTC TCA ACC ATT AGT GGT GGT GGT ACT TAC ACC TAC TAT CAA GAC AGT GTG AAG GGG CGG TTC ACC ATC TCC AGA GAC AAT TCC AAG AAC ACG CTG TAT CTG CAA ATG AAC AGC CTG AGA GCC GAG GAC ACG GCC GTA TAT TAC TGT GCG TCC ATG GAC TAC TGG GGG CAA GGG ACC ACG GTC ACC GTC TCC TCA GCA TCC ACC AAG GGC CCA TCG GTC TTC CCG CTA GCA CCC TGC TCC AGG AGC ACC TCC GAG AGC ACA GCC GCC CTG GGC TGC CTG GTC AAG GAC TAC TTC CCC GAA CCA GTG ACG GTG TCG TGG AAC TCA GGC GCC CTG ACC AGC GGC GTG CAC ACC TTC CCG GCT GTC CTA CAG TCC TCA GGA CTC TAC TCC CTC AGC AGC GTG GTG ACC GTG CCC TCC AGC AGC TTG GGC ACG AAG ACC TAC ACC TGC AAC GTA GAT CAC AAG CCC AGC AAC ACC AAG GTG GAC AAG AGA GTT GAG TCC AAA TAT GGT CCC CCA TGC CCA CCA TGC CCA GCA CCT GAG TTC CTG GGG GGA CCA TCA GTC TTC CTG TTC CCC CCA AAA CCC AAG GAC ACT CTC ATG ATC TCC CGG ACC CCT GAG GTC ACG TGC GTG GTG GTG GAC GTG AGC CAG GAA GAC CCC GAG GTC CAG TTC AAC TGG TAC GTG GAT GGC GTG GAG GTG CAT AAT GCC AAG ACA AAG CCG CGG GAG GAG CAG TTC AAC AGC ACG TAC CGT GTG GTC AGC GTC CTC ACC GTC CTG CAC CAG GAC TGG CTG AAC GGC AAG GAG TAC AAG TGC AAG GTC TCC AAC AAA GGC CTC CCG TCC TCC ATC GAG AAA ACC ATC TCC AAA GCC AAA GGG CAG CCC CGA GAG CCA CAG GTG TAC ACC CTG CCC CCA TCC CAG GAG GAG ATG ACC AAG AAC CAG GTC AGC CTG ACC TGC CTG GTC AAA GGC TTC TAC CCC AGC GAC ATC GCC GTG GAG TGG GAG AGC AAT GGG CAG CCG GAG AAC AAC TAC AAG ACC ACG CCT CCC GTG CTG GAC TCC GAC GGC TCC TTC TTC CTC TAC AGC AGG CTA ACC GTG GAC AAG AGC AGG TGG CAG GAG GGG AAT GTC TTC TCA TGC TCC GTG ATG CAT GAG GCT CTG CAC AAC CAC TAC ACA CAG AAG AGC CTC TCC CTG TCT CTG GGT AAA

In some embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin light chain polypeptide encoded by a nucleotide sequence comprising SEQ ID NO:10.
Nucleotide sequence encoding anti-TIM-3 antibody light chain polypeptide (SEQ ID NO:10)
GAC ATC CAG ATG ACC CAG TCT CCA TCC TCC CTG TCT GCA TCT GTA GGA GAC AGA GTC ACC ATC ACT TGC CGG GCA AGT CAG AGC ATT AGG AGG TAT TTA AAT TGG TAT CAC CAG AAA CCA GGG AAA GCC CCT AAG CTC CTG ATC TAT GGT GCA TCC ACC TTG CAA AGT GGG GTC CCA TCA AGG TTC AGT GGT AGT GGA TCT GGG ACA GAT TTC ACT CTC ACC ATC AGC AGT CTG CAA CCT GAA GAT TTT GCA GTG TAT TAC TGT CAA CAG AGT CAC AGT GCC CCC CTC ACT TTC GGC GGA GGG ACC AAG GTG GAG ATC AAA CGA ACT GTG GCT GCA CCA TCT GTC TTC ATC TTC CCG CCA TCT GAT GAG CAA TTG AAA TCT GGA ACT GCC TCT GTT GTG TGC CTG CTG AAT AAC TTC TAT CCC AGA GAG GCC AAA GTA CAG TGG AAG GTG GAT AAC GCC CTC CAA TCG GGT AAC TCC CAG GAG AGT GTC ACA GAG CAG GAC AGC AAG GAC AGC ACC TAC AGC CTC AGC AGC ACC CTG ACG CTG AGC AAA GCA GAC TAC GAG AAA CAC AAA GTC TAC GCC TGC GAA GTC ACC CAT CAG GGC CTC AGC TCG CCC GTC ACA AAG AGC TTC AAC AGG GGA GAG TGT

In some embodiments, the PD-1 binding agent comprises an immunoglobulin heavy chain polypeptide encoded by a nucleotide sequence comprising SEQ ID NO:19.
SEQ ID NO:19 - Nucleotide sequence encoding an immunoglobulin heavy chain polypeptide of a PD-1 binding agent GAG GTG CAG CTG TTG GAG TCT GGG GGA GGC TTG GTA CAG CCT GGG GGG TCC CTG AGA CTC TCC TGT GCA GCC TCT GGA TTC ACT TTC AGT AGC TAT GAC ATG TCT TGG GTC CGC CAG GCT CCA GGG AAG GGG CTG GAG TGG GTC TCA ACC ATT AGT GGT GGT GGT AGT TAC ACC TAC TAT CAA GAC AGT GTG AAG GGG CGG TTC ACC ATC TCC AGA GAC AAT TCC AAG AAC ACG CTG TAT CTG CAA ATG AAC AGC CTG AGA GCC GAG GAC ACG GCC GTA TAT TAC TGT GCG TCC CCT TAC TAT GCT ATG GAC TAC TGG GGG CAA GGG ACC ACG GTC ACC GTC TCC TCA GCA TCC ACC AAG GGC CCA TCG GTC TTC CCG CTA GCA CCC TGC TCC AGG AGC ACC TCC GAG AGC ACA GCC GCC CTG GGC TGC CTG GTC AAG GAC TAC TTC CCC GAA CCA GTG ACG GTG TCG TGG AAC TCA GGC GCC CTG ACC AGC GGC GTG CAC ACC TTC CCG GCT GTC CTA CAG TCC TCA GGA CTC TAC TCC CTC AGC AGC GTG GTG ACC GTG CCC TCC AGC AGC TTG GGC ACG AAG ACC TAC ACC TGC AAC GTA GAT CAC AAG CCC AGC AAC ACC AAG GTG GAC AAG AGA GTT GAG TCC AAA TAT GGT CCC CCA TGC CCA CCA TGC CCA GCA CCT GAG TTC CTG GGG GGA CCA TCA GTC TTC CTG TTC CCC CCA AAA CCC AAG GAC ACT CTC ATG ATC TCC CGG ACC CCT GAG GTC ACG TGC GTG GTG GTG GAC GTG AGC CAG GAA GAC CCC GAG GTC CAG TTC AAC TGG TAC GTG GAT GGC GTG GAG GTG CAT AAT GCC AAG ACA AAG CCG CGG GAG GAG CAG TTC AAC AGC ACG TAC CGT GTG GTC AGC GTC CTC ACC GTC CTG CAC CAG GAC TGG CTG AAC GGC AAG GAG TAC AAG TGC AAG GTC TCC AAC AAA GGC CTC CCG TCC TCC ATC GAG AAA ACC ATC TCC AAA GCC AAA GGG CAG CCC CGA GAG CCA CAG GTG TAC ACC CTG CCC CCA TCC CAG GAG GAG ATG ACC AAG AAC CAG GTC AGC CTG ACC TGC CTG GTC AAA GGC TTC TAC CCC AGC GAC ATC GCC GTG GAG TGG GAG AGC AAT GGG CAG CCG GAG AAC AAC TAC AAG ACC ACG CCT CCC GTG CTG GAC TCC GAC GGC TCC TTC TTC CTC TAC AGC AGG CTA ACC GTG GAC AAG AGC AGG TGG CAG GAG GGG AAT GTC TTC TCA TGC TCC GTG ATG CAT GAG GCT CTG CAC AAC CAC TAC ACA CAG AAG AGC CTC TCC CTG TCT CTG GGT AAA

In some embodiments, the PD-1-binding agent comprises an immunoglobulin light chain polypeptide encoded by a nucleotide sequence comprising SEQ ID NO:20.
SEQ ID NO:20 - Nucleotide sequence encoding an immunoglobulin light chain polypeptide of a PD-1 binding agent GAC ATC CAG TTG ACC CAG TCT CCA TCC TTC CTG TCT GCA TAT GTA GGA GAC AGA GTC ACC ATC ACT TGC AAG GCC AGT CAG GAT GTG GGT ACT GCT GTA GCC TGG TAT CAG CAA AAA CCA GGG AAA GCC CCT AAG CTC CTG ATC TAT TGG GCA TCC ACC CTG CAC ACT GGG GTC CCA TCA AGG TTC AGC GGC AGT GGA TCT GGG ACA GAA TTC ACT CTC ACA ATC AGC AGC CTG CAG CCT GAA GAT TTT GCA ACT TAT TAC TGT CAG CAT TAT AGC AGC TAT CCG TGG ACG TTT GGC CAG GGG ACC AAG CTG GAG ATC AAA CGG ACT GTG GCT GCA CCA TCT GTC TTC ATC TTC CCG CCA TCT GAT GAG CAA TTG AAA TCT GGA ACT GCC TCT GTT GTG TGC CTG CTG AAT AAC TTC TAT CCC AGA GAG GCC AAA GTA CAG TGG AAG GTG GAT AAC GCC CTC CAA TCG GGT AAC TCC CAG GAG AGT GTC ACA GAG CAG GAC AGC AAG GAC AGC ACC TAC AGC CTC AGC AGC ACC CTG ACG CTG AGC AAA GCA GAC TAC GAG AAA CAC AAA GTC TAC GCC TGC GAA GTC ACC CAT CAG GGC CTC AGC TCG CCC GTC ACA AAG AGC TTC AAC AGG GGA GAG TGT

In some embodiments, the anti-TIM-3 antibody agent and/or PD-1-binding agent are expressed from a vector that includes one or more nucleic acid sequences encoding an immunoglobulin heavy chain variable domain polypeptide and/or an immunoglobulin light chain variable domain polypeptide. In some embodiments, the anti-TIM-3 antibody agent and/or PD-1-binding agent are expressed from a vector that includes one or more nucleic acid sequences encoding an immunoglobulin heavy chain polypeptide and/or an immunoglobulin light chain polypeptide. The vector can be, for example, a plasmid, episome, cosmid, viral vector (e.g., retroviral or adenoviral), or phage. Suitable vectors and methods for vector preparation are well known in the art (see, for example, Sambrook et al., Molecular Cloning, a
Laboratory Manual, 3rd edition, Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (2001); and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates and John Wiley & Sons, New York, N.Y. (1994).

In some embodiments, the vector for expression of the anti-TIM-3 antibody agent and/or the PD-1 binding agent further comprises an expression control sequence, e.g., a promoter, an enhancer, a polyadenylation signal, a transcription terminator, an internal ribosome entry site (IRES), etc., that effects expression of the coding sequence in the host cell. Exemplary expression control sequences are known in the art and are described, for example, in Goeddel, Gene Expression Technology: Methods in Enzymology, Vol. 185, Academic Press, San Diego, Calif. (1990).

A vector containing a nucleic acid encoding an anti-TIM-3 antibody agent and/or a PD-1 binding agent of the present disclosure can be introduced into a host cell capable of expressing the polypeptide encoded by the nucleic acid, including any suitable prokaryotic or eukaryotic cell. Some preferred qualities of host cells include easy and reliable growth, reasonably fast growth rates, having a well-characterized expression system, and/or easy/efficient transformation or transfection.

In some embodiments, mammalian cells are utilized. Several suitable mammalian host cells are known in the art, and many are available from the American Type Culture Collection (ATCC, Manassas, VA). Examples of suitable mammalian cells include, but are not limited to, Chinese hamster ovary cells (CHO) (ATCC No. CCL61), CHO DHFR cells (Urlaub et al., Proc. Natl. Acad. Sci. USA, 97:4216-4220 (1980)), human embryonic kidney (HEK) 293 or 293T cells (ATCC No. CRL1573), and 3T3 cells (ATCC No. CCL92). Other suitable mammalian cell lines are the monkey COS-1 (ATCC No. CRL1650) and COS-7 cell lines (ATCC No. CRL1651), and the CV-1 cell line (ATCC No. CCL70).

Further exemplary mammalian host cells include primate and rodent cell lines, including transformed cell lines. Normal diploid cells, cell lines derived from in vitro culture of primary tissues, and primary explants are also suitable. Other suitable mammalian cell lines include, but are not limited to, mouse neuroblastoma N2A cells, HeLa, mouse L-929 cells, and BHK or HaK hamster cell lines, all of which are available from the ATCC. Methods for selecting suitable mammalian host cells and methods for transforming, culturing, amplifying, screening, and purifying the cells are known in the art.

In some embodiments, the mammalian cell is a human cell. For example, the mammalian cell can be a human lymphoid or lymphoid-derived cell line, e.g., a cell line of pre-B lymphocytic origin. Examples of human lymphoid cell lines include, but are not limited to, RAMOS (CRL-1596), Daudi (CCL-213), EB-3 (CCL-85), DT40 (CRL-2111), 18-81 (Jack et al., Proc. Natl. Acad. Sci. USA, 85:1581-1585 (1988)), Raji cells (CCL-86), and derivatives thereof.

In some embodiments, the anti-TIM-3 antibody agent is formulated as a pharmaceutical composition containing one or a combination of monoclonal antibodies or antigen-binding portions thereof, and is formulated with a pharma- ceutically acceptable carrier. The anti-TIM-3 antibody agent may be formulated alone or in combination with other drugs (e.g., as an adjuvant). For example, the anti-TIM-3 antibody agent may be administered in combination with other agents for the treatment or prevention of a disease (e.g., cancer) disclosed herein.

Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage. The compositions may be formulated as solutions, microemulsions, liposomes, or ordered structures suitable for high drug concentration. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. In many cases, it will be preferable to include an isotonic agent in the composition, for example, sugar, polyalcohol such as mannitol, sorbitol, or sodium chloride. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.

Sterile injectable solutions can be prepared by incorporating the required amount of active compound in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterile microfiltration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and the required other ingredients enumerated above. Sterile powders are facilitated in the preparation of sterile injectable solutions, and the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization), which yield a powder containing the active ingredient and any additional desired ingredients from a previously sterile-filtered solution.

In some embodiments, the therapeutic composition is formulated as a sterile liquid. In some embodiments, the composition is free of visible particles. In some embodiments, the composition is formulated in a buffer. In some embodiments, the anti-TIM-3 antibody agent is stored at 2-8° C. In some embodiments, the drug product of the present disclosure is preservative-free.
General Protocol

As described herein, the methods provided include administering an anti-TIM-3 antibody agent to a patient, subject, or subject population (e.g., according to a regimen that achieves a clinical benefit).

The methods provided may result in a variety of benefits (e.g., clinical benefit). In embodiments, the methods described herein achieve a clinical benefit. In embodiments, the clinical benefit is stable disease (SD). In embodiments, the clinical benefit is a partial response (PR). In embodiments, the clinical benefit is a complete response (CR).

In embodiments, the combination therapy achieves the clinical benefit of each therapy administered to the patient. For example, the subject may be resistant to treatment with an agent that inhibits PD-1, or the subject may be refractory to treatment with an agent that inhibits PD-1. In embodiments, the methods described herein sensitize the subject to treatment with an agent that inhibits PD-1. Thus, in embodiments, the benefit of the combination therapy that includes administration of a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody described herein) and a PD-1 inhibitor (e.g., any anti-PD-1 antibody described herein) is to achieve or improve the clinical benefit of the PD-1 inhibitor (e.g., any anti-PD-1 antibody described herein).

In an embodiment, the patient or subject is an animal. In an embodiment, the patient or subject is a human.

In embodiments, administration of the anti-TIM-3 antibody agent is parenteral administration. In embodiments, parenteral administration is intravenous administration. In embodiments, intravenous administration is intravenous infusion.

In some embodiments, the regimen includes at least one parenteral dose of an anti-TIM-3 antibody agent. In some embodiments, the regimen includes multiple parenteral doses.

In some embodiments, the parenteral dose is a dose of the anti-TIM-3 antibody agent in the range of about 5 to about 5000 mg (e.g., about 5 mg, about 10 mg, about 50 mg, about 100 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 2000 mg, about 3000 mg, about 4000 mg, about 5000 mg, or a range defined by any two of the foregoing values). In some embodiments, the parenteral dose of the anti-TIM-3 antibody agent is 500 mg or 1000 mg. In some embodiments, the parenteral dose of the anti-TIM-3 antibody agent is about 100 mg, about 300 mg, or about 1200 mg.

In some embodiments, the dose is an amount relative to body weight. In some embodiments, a parenteral dose of an anti-TIM-3 antibody agent is in the range of about 0.01 mg/kg to 100 mg/kg animal or human body weight, although doses below or above this exemplary range are also within the scope of the invention. The dose (e.g., a daily parenteral dose) can be about 0.01 mg/kg to about 50 mg/kg total body weight (e.g., about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 12 mg/kg, about 15 mg/kg, about 20 mg/kg, or a range defined by any two of the foregoing values).

In some embodiments, the composition delivering the anti-TIM-3 antibody agent is administered to the patient at a dose of 0.1, 1, 3, or 10 mg/kg. In some embodiments, the composition delivering the anti-TIM-3 antibody agent is administered according to a regimen including a dose of 0.1, 1, 3, or 10 mg/kg once every two weeks. In some embodiments, the composition delivering the anti-TIM-3 antibody agent is administered according to a regimen including a dose of 0.1, 1, 3, or 10 mg/kg once every three weeks. In some embodiments, the composition delivering the anti-TIM-3 antibody agent is administered according to a regimen including a dose of 0.1, 1, 3, or 10 mg/kg once every four weeks.

In some embodiments, the composition delivering the anti-TIM-3 antibody agent is administered to the patient at a dose of about 100 to about 500 mg (e.g., 200 to 500 mg). In some embodiments, the composition delivering the anti-TIM-3 antibody agent is administered according to a regimen including a dose of about 100 to about 500 mg (e.g., 200 mg, 300 mg, 400 mg, 500 mg) once every two weeks. In some embodiments, the composition delivering the anti-TIM-3 antibody agent is administered according to a regimen including a dose of about 100 to about 500 mg (e.g., 200 mg, 300 mg, 400 mg, 500 mg) once every three weeks. In some embodiments, the composition delivering the anti-TIM-3 antibody agent is administered according to a regimen including a dose of about 100 to about 500 mg (e.g., 200 mg, 300 mg, 400 mg, 500 mg) once every four weeks.

In some embodiments, the composition delivering the anti-TIM-3 antibody agent is administered to the patient at a dose of about 800 to about 1500 mg (e.g., 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg). In some embodiments, the composition delivering the anti-TIM-3 antibody agent is administered according to a regimen including a dose of about 800 to about 1500 mg (e.g., 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg) once every four weeks. In some embodiments, the composition delivering the anti-TIM-3 antibody agent is administered according to a regimen including a dose of about 800 to about 1500 mg (e.g., 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg) once every six weeks. In some embodiments, the composition delivering the anti-TIM-3 antibody agent is administered according to a regimen including a dose of about 800 to about 1500 mg (e.g., 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg) once every eight weeks.

In an embodiment, the dose (e.g., a therapeutically effective dose, a dose administered by a composition delivering an anti-TIM-3 antibody drug, or a parenteral dose) is about 1 mg/kg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every two weeks (Q2W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every three weeks (Q3W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every four weeks (Q4W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every five weeks (Q5W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every six weeks (Q6W). In an embodiment, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is administered intravenously. In embodiments, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is an intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for monotherapy. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042)). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody drug. In embodiments, the anti-TIM-3 antibody drug is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:4.

In an embodiment, the dose (e.g., a therapeutically effective dose, a dose administered by a composition delivering an anti-TIM-3 antibody drug, or a parenteral dose) is about 3 mg/kg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every two weeks (Q2W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every three weeks (Q3W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every four weeks (Q4W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every five weeks (Q5W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every six weeks (Q6W). In an embodiment, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is administered intravenously. In embodiments, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is an intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for monotherapy. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042)). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody drug. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:4.

In an embodiment, the dose (e.g., a therapeutically effective dose, a dose administered by a composition delivering an anti-TIM-3 antibody drug, or a parenteral dose) is about 10 mg/kg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every two weeks (Q2W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every three weeks (Q3W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every four weeks (Q4W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every five weeks (Q5W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every six weeks (Q6W). In an embodiment, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is administered intravenously. In embodiments, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is an intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for monotherapy. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042)). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody drug. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:4.

In embodiments, the dose (e.g., a therapeutically effective dose, a dose administered by a composition delivering an anti-TIM-3 antibody agent, or a parenteral dose) is about 100-1500 mg of a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In embodiments, the dose is administered (e.g., intravenously, such as by intravenous infusion) once per week (Q1W). In embodiments, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every two weeks (Q2W). In embodiments, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every three weeks (Q3W). In embodiments, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every four weeks (Q4W). In embodiments, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every five weeks (Q5W). In embodiments, administration of the dose (e.g., intravenous administration, such as intravenous infusion) is once every six weeks (Q6W). In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody drug) is intravenous. In embodiments, the TIM-3 inhibitor (e.g., anti-TIM-3 antibody drug) is an intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody drug) is for monotherapy. In embodiments, administration of the TIM-3 inhibitor (e.g., anti-TIM-3 antibody drug) is for combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042)). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody drug. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:4.

In an embodiment, the dose (e.g., a therapeutically effective dose, a dose administered by a composition delivering an anti-TIM-3 antibody drug, or a parenteral dose) is about 100 mg of a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every two weeks (Q2W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every three weeks (Q3W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every four weeks (Q4W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every five weeks (Q5W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every six weeks (Q6W). In an embodiment, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is administered intravenously. In embodiments, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is an intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for monotherapy. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042)). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody drug. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered by a composition delivering an anti-TIM-3 antibody agent, or a parenteral dose) is about 200 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every two weeks (Q2W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every three weeks (Q3W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every four weeks (Q4W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every five weeks (Q5W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every six weeks (Q6W). In an embodiment, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is administered intravenously. In embodiments, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is an intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for monotherapy. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042)). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody drug. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered by a composition delivering an anti-TIM-3 antibody agent, or a parenteral dose) is about 300 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every two weeks (Q2W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every three weeks (Q3W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every four weeks (Q4W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every five weeks (Q5W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every six weeks (Q6W). In an embodiment, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is administered intravenously. In embodiments, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is an intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for monotherapy. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042)). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody drug. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered by a composition delivering an anti-TIM-3 antibody agent, or a parenteral dose) is about 400 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every two weeks (Q2W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every three weeks (Q3W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every four weeks (Q4W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every five weeks (Q5W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every six weeks (Q6W). In an embodiment, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is administered intravenously. In embodiments, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is an intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for monotherapy. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042)). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody drug. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered by a composition delivering an anti-TIM-3 antibody agent, or a parenteral dose) is about 500 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every two weeks (Q2W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every three weeks (Q3W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every four weeks (Q4W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every five weeks (Q5W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every six weeks (Q6W). In an embodiment, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is administered intravenously. In embodiments, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is an intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for monotherapy. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042)). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody drug. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered by a composition delivering an anti-TIM-3 antibody agent, or a parenteral dose) is about 600 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every two weeks (Q2W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every three weeks (Q3W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every four weeks (Q4W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every five weeks (Q5W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every six weeks (Q6W). In an embodiment, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is administered intravenously. In embodiments, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is an intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for monotherapy. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042)). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody drug. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered by a composition delivering an anti-TIM-3 antibody agent, or a parenteral dose) is about 700 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every two weeks (Q2W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every three weeks (Q3W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every four weeks (Q4W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every five weeks (Q5W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every six weeks (Q6W). In an embodiment, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is administered intravenously. In embodiments, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is an intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for monotherapy. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042)). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody drug. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered by a composition delivering an anti-TIM-3 antibody agent, or a parenteral dose) is about 800 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every two weeks (Q2W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every three weeks (Q3W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every four weeks (Q4W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every five weeks (Q5W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every six weeks (Q6W). In an embodiment, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is administered intravenously. In embodiments, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is an intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for monotherapy. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042)). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody drug. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered by a composition delivering an anti-TIM-3 antibody agent, or a parenteral dose) is about 900 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every two weeks (Q2W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every three weeks (Q3W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every four weeks (Q4W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every five weeks (Q5W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every six weeks (Q6W). In an embodiment, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody agent) is administered intravenously. In embodiments, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is an intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for monotherapy. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042)). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody drug. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered by a composition delivering an anti-TIM-3 antibody drug, or a parenteral dose) is about 1000 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every two weeks (Q2W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every three weeks (Q3W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every four weeks (Q4W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every five weeks (Q5W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every six weeks (Q6W). In an embodiment, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is administered intravenously. In embodiments, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is an intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for monotherapy. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042)). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody drug. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered by a composition delivering an anti-TIM-3 antibody drug, or a parenteral dose) is about 1100 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every two weeks (Q2W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every three weeks (Q3W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every four weeks (Q4W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every five weeks (Q5W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every six weeks (Q6W). In an embodiment, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is administered intravenously. In embodiments, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is an intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for monotherapy. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042)). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody drug. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered by a composition delivering an anti-TIM-3 antibody drug, or a parenteral dose) is about 1200 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every two weeks (Q2W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every three weeks (Q3W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every four weeks (Q4W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every five weeks (Q5W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every six weeks (Q6W). In an embodiment, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is administered intravenously. In embodiments, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is an intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for monotherapy. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042)). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody drug. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered by a composition delivering an anti-TIM-3 antibody drug, or a parenteral dose) is about 1300 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every two weeks (Q2W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every three weeks (Q3W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every four weeks (Q4W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every five weeks (Q5W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every six weeks (Q6W). In an embodiment, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is administered intravenously. In embodiments, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is an intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for monotherapy. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042)). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody drug. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered by a composition delivering an anti-TIM-3 antibody drug, or a parenteral dose) is about 1400 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every two weeks (Q2W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every three weeks (Q3W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every four weeks (Q4W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every five weeks (Q5W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every six weeks (Q6W). In an embodiment, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is administered intravenously. In embodiments, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is an intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for monotherapy. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042)). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody drug. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:4.

In any of the methods described herein, the dose (e.g., a therapeutically effective dose, a dose administered by a composition delivering an anti-TIM-3 antibody drug, or a parenteral dose) is about 1500 mg of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every two weeks (Q2W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every three weeks (Q3W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every four weeks (Q4W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every five weeks (Q5W). In an embodiment, the dose is administered (e.g., intravenously, such as by intravenous infusion) once every six weeks (Q6W). In an embodiment, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is administered intravenously. In embodiments, the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is an intravenous infusion. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for monotherapy. In embodiments, administration of the TIM-3 inhibitor (e.g., an anti-TIM-3 antibody drug) is for combination therapy (e.g., in combination with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as TSR-042)). In embodiments, the TIM-3 inhibitor is an anti-TIM-3 antibody drug. In embodiments, the TIM-3 inhibitor is TSR-022. In embodiments, the anti-TIM-3 antibody agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:3, and an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% overall identity to SEQ ID NO:4.

Therapeutic or prophylactic efficacy can be monitored by periodic evaluation of the treated patient. For repeated administration over several days or longer depending on the condition, treatment can be repeated until a desired suppression of disease symptoms occurs. However, other dosing regimens may be useful and are within the scope of the invention. The desired dosage can be delivered by a single bolus administration of the composition, by multiple boluses of the composition, or by continuous infusion administration of the composition.

In some embodiments, the anti-TIM-3 antibody agent is administered to a patient or subject population that has responded to a prior therapy. In some embodiments, the patient or subject population has responded to a prior cancer therapy.

In some embodiments, the anti-TIM-3 antibody agent is administered to a patient or subject population that has not responded to a prior therapy. In some embodiments, the patient or subject population has not received or responded to a prior cancer therapy.

In embodiments, the subject is resistant to treatment with an agent that inhibits PD-1. In embodiments, the subject is refractory to treatment with an agent that inhibits PD-1. In embodiments, the methods described herein sensitize the subject to treatment with an agent that inhibits PD-1.

In embodiments, the anti-TIM-3 antibody agents described herein are administered in combination with one or more additional therapies (e.g., therapies described herein). That is, a subject is treated with an anti-TIM-3 antibody agent and one or more additional therapies are administered to the subject such that the subject receives each of the therapies.

In an embodiment, the additional therapy is surgery. In an embodiment, the additional therapy is radiation therapy. In an embodiment, the additional therapy is chemotherapy. In an embodiment, the additional therapy is immunotherapy.

In some embodiments, the anti-TIM-3 antibody agent is administered as a monotherapy.

In some embodiments, the anti-TIM-3 antibody agent is administered in a combination therapy. In embodiments, the anti-TIM-3 antibody agent is administered in combination with another treatment modality (e.g., one or more of surgery, radiation therapy, chemotherapy, or immunotherapy). In embodiments, the anti-TIM-3 antibody agent is administered in combination with surgery. In embodiments, the anti-TIM-3 antibody agent is administered in combination with radiation therapy. In some embodiments, the anti-TIM-3 antibody agent is administered in combination with chemotherapy. In embodiments, the anti-TIM-3 antibody agent is administered in combination with immunotherapy.

In some embodiments, the anti-TIM-3 antibody agent is administered simultaneously or sequentially with an additional therapeutic agent, e.g., another antibody agent (e.g., an antibody agent that binds to PD-1) and/or a chemotherapeutic agent (e.g., niraparib). In some embodiments, the anti-TIM-3 antibody agent is administered before, during, or after administration of the additional therapeutic agent. In some embodiments, the anti-TIM-3 antibody agent is administered before, during, or after administration of a chemotherapeutic agent (e.g., niraparib).

The anti-TIM-3 antibody agent may be administered alone or in combination with other drugs (e.g., as an adjuvant). For example, the anti-TIM-3 antibody agent may be administered in combination with other agents for the treatment or prevention of a disease (e.g., cancer) disclosed herein. In this regard, the anti-TIM-3 antibody agent may be used in combination with at least one other anti-cancer agent, including, for example, any chemotherapeutic agent known in the art, ionizing radiation, small molecule anti-cancer agents, cancer vaccines, biological therapies (e.g., other monoclonal antibodies, cancer-killing viruses, gene therapy, and adoptive T cell transfer), and/or surgery.

Concurrent or sequential administration of an anti-TIM-3 antibody agent and an additional therapeutic agent is referred to herein as “combination therapy.” In combination therapy, the anti-TIM-3 antibody agent can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before) or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) administration of the additional therapeutic agent to a subject in need thereof. In some embodiments, the anti-TIM-3 antibody agent and the additional therapeutic agent are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 to 2 hours apart, 2 to 3 hours apart, 3 to 4 hours apart, 4 to 5 hours apart, 5 to 6 hours apart, 6 to 7 hours apart, 7 to 8 hours apart, 8 to 9 hours apart, 9 to 10 hours apart, 10 to 11 hours apart, 11 to 12 hours apart, no more than 24 hours apart, or no more than 48 hours apart.
PARP inhibitors

In an embodiment, the additional therapy is a poly(ADP-ribose) polymerase (PARP) inhibitor.

In embodiments, the PARP inhibitor inhibits PARP-1 and/or PARP-2. In some embodiments, the agent is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In related embodiments, the agent is ABT-767, AZD 2461, BGB-290, BGP 15, CEP 8983, CEP 9722, DR 2313, E7016, E7449, fluzoparib (SHR 3162), IMP 4297, INO1001, JPI 289, JPI 547, monoclonal antibody B3-LysPE40 conjugate, MP 124, niraparib (ZEJULA) (MK-4827), NU 1025, NU 1064, NU 1076, NU1085, olaparib (AZD2281), ONO2231, PD 128763, R 503, R554, rucaparib (RUBRACA) (AG-014699, PF-01367338), SBP 101, SC 101914, simmiparib, talazoparib (BMN-673), veliparib (ABT-888), WW 46, 2-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-ol, and salts or derivatives thereof. In related embodiments, the agent is niraparib, olaparib, rucaparib, talazoparib, veliparib, or salts or derivatives thereof. In certain embodiments, the agent is niraparib or a salt or derivative thereof. In certain embodiments, the agent is olaparib or a salt or derivative thereof. In certain embodiments, the agent is rucaparib or a salt or derivative thereof. In certain embodiments, the agent is talazoparib or a salt or derivative thereof. In certain embodiments, the agent is veliparib or a salt or derivative thereof.

Niraparib ((3S)-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl}phenyl]piperidine) is an orally available, potent poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP)-1 and -2 inhibitor. See WO 2008/084261 (published July 17, 2008), WO 2009/087381 (published July 16, 2009), and PCT/US17/40039 (filed June 29, 2017), each of which is incorporated by reference in its entirety. Niraparib can be prepared according to Scheme 1 of WO 2008/084261.

In some embodiments, niraparib may be prepared as a pharma- ceutically acceptable salt. One of skill in the art will appreciate that such salt forms may exist as solvates or hydrated polymorphic forms. In some embodiments, niraparib is prepared in the form of a hydrate.

In certain embodiments, Niraparib is prepared in the form of a tosylate salt. In some embodiments, Niraparib is prepared in the form of a tosylate monohydrate. The molecular structure of Niraparib tosylate monohydrate is shown below.

Niraparib is a potent and selective inhibitor of PARP-1 and PARP-2 with IC50 values of 3.8 and 2.1 nM, respectively, making it at least 100-fold more selective than other PARP family members. Niraparib inhibits PARP activity stimulated as a result of DNA damage caused by the addition of hydrogen peroxide in a variety of cell lines with an _IC50 of approximately ₄ nM and an IC90 value of ₅₀ nM.

In an embodiment, niraparib is administered at a dose equivalent to about 100 mg of niraparib free base (e.g., a pharma- ceutically acceptable salt of niraparib, such as niraparib tosylate monohydrate, is administered at a dose equivalent to about 100 mg of niraparib free base). In an embodiment, niraparib is administered at a dose equivalent to about 200 mg of niraparib free base (e.g., a pharma- ceutically acceptable salt of niraparib, such as niraparib tosylate monohydrate, is administered at a dose equivalent to about 200 mg of niraparib free base). In an embodiment, niraparib is administered at a dose equivalent to about 300 mg of niraparib free base (e.g., a pharma- ceutically acceptable salt of niraparib, such as niraparib tosylate monohydrate, is administered at a dose equivalent to about 300 mg of niraparib free base).
Checkpoint inhibitors

In embodiments, the additional therapy is immunotherapy. In embodiments, the immunotherapy includes administration of one or more additional immune checkpoint inhibitors (e.g., one, two, three, four, or more additional immune checkpoint inhibitors).

Exemplary immune checkpoint inhibition targets include: PD-1 (e.g., inhibition via anti-PD-1, anti-PD-L1, or anti-PD-L2 therapy), CTLA-4, TIM-3, TIGIT, LAG (e.g., LAG-3), CEACAM (e.g., CEACAM-1, -3, and/or -5), VISTA, BTLA, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GALS, adenosine, TGFR (e.g., TGFR beta), B7-H1, B7-H4 (VTCN1), OX-40, CD137, CD40, IDO, and CSF1R. Thus, agents that inhibit any of these molecules can be used in combination with the anti-TiM-3 therapies described herein.

In embodiments, the immune checkpoint inhibitor is an agent that inhibits PD-1, CTLA-4, LAG-3, TIGIT, IDO, or CSF1R.

In embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor. In embodiments, the PD-1 inhibitor is a PD-1 binding agent (e.g., an antibody, antibody conjugate, or antigen-binding fragment thereof). In embodiments, the PD-1 inhibitor is a PD-L1 or PD-L2 binding agent (e.g., an antibody, antibody conjugate, or antigen-binding fragment thereof). In embodiments, the PD-1 inhibitor is nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, TSR-042, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283, MGA012, BI-754091, IBI-308, camrelizumab (HR-301210), BCD-100, JS-001, CX-072, BGB-A333/AMP-514 (MEDI-0680), AGEN-2034, CS1001, Sym-021, SHR-1316, PF-06801591, LZM009, KN-035, AB122, genolimuzumab (CBT-501), FAZ-053, CK-301, AK 104, or GLS-010, or any of the PD-1 antibodies disclosed in WO 2014/179664. In an embodiment, the PD-1 inhibitor is TSR-042. In some embodiments, the PD-1 inhibitor (e.g., TSR-042) is administered according to a regimen comprising administering about a 500 mg dose once every three weeks for four doses, followed by at least one about 1,000 mg dose once every six weeks after the fourth dose of about 500 mg. In some embodiments, additional about 1,000 mg doses are administered once every six weeks after the first dose of about 1000 mg until no further clinical benefit is achieved. In some specific embodiments, the PD-1 inhibitor (e.g., TSR-042) is administered according to a dosing regimen comprising 500 mg Q3W for four cycles, followed by 1000 mg Q6W.

In embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor (e.g., an antibody, antibody conjugate, or antigen-binding fragment thereof). In embodiments, the CTLA-4 inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the CTLA-4 inhibitor is a small molecule. In embodiments, the CTLA-4 inhibitor is a CTLA-4 binding agent. In embodiments, the CTLA-4 inhibitor is an antibody, antibody conjugate, or antigen-binding fragment thereof. In embodiments, the CTLA-4 inhibitor is ipilimumab (Yervoy), AGEN1884, or tremelimumab.

In embodiments, the immune checkpoint inhibitor is a LAG-3 inhibitor (e.g., an antibody, antibody conjugate, or antigen-binding fragment thereof). In embodiments, the LAG-3 inhibitor is a small molecule, nucleic acid, polypeptide (e.g., an antibody), carbohydrate, lipid, metal, or toxin. In embodiments, the LAG-3 inhibitor is a small molecule. In embodiments, the LAG-3 inhibitor is a LAG-3 binding agent. In embodiments, the LAG-3 inhibitor is an antibody, antibody conjugate, or antigen-binding fragment thereof. In embodiments, the LAG-3 inhibitor is IMP321, BMS-986016, GSK2831781, Novartis
LAG525, or a LAG-3 inhibitor as described in WO2016/126858, WO2017/019894, or WO2015/138920, each of which is incorporated by reference in its entirety.

In embodiments, the immune checkpoint inhibitor is a TIGIT inhibitor (e.g., an antibody, antibody conjugate, or antigen-binding fragment thereof). In embodiments, the TIGIT inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the TIGIT inhibitor is a small molecule. In embodiments, the TIGIT inhibitor is a TIGIT binding agent. In embodiments, the TIGIT inhibitor is an antibody, antibody conjugate, or antigen-binding fragment thereof. In embodiments, the TIGIT inhibitor is MTIG7192A, BMS-986207, or OMP-31M32.

In embodiments, the immune checkpoint inhibitor is an IDO inhibitor. In embodiments, the IDO inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the IDO inhibitor is a small molecule. In embodiments, the IDO inhibitor is an IDO binding agent. In embodiments, the IDO inhibitor is an antibody, an antibody conjugate, or an antigen-binding fragment thereof.

In embodiments, the immune checkpoint inhibitor is a CSF1R inhibitor. In embodiments, the CSF1R inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the CSF1R inhibitor is a small molecule. In embodiments, the CSF1R inhibitor is a CSF1R binding agent. In embodiments, the CSF1R inhibitor is an antibody, an antibody conjugate, or an antigen-binding fragment thereof.

In an embodiment, the method includes administering a TIM-3 inhibitor along with at least two of the immune checkpoint inhibitors. In an embodiment, the method includes administering a third checkpoint inhibitor. In an embodiment, the method includes administering a TIM-3 inhibitor along with a PD-1 inhibitor and a LAG-3 inhibitor, such that the subject receives all three. In an embodiment, the method includes administering a TIM-3 inhibitor along with a PD-1 inhibitor, a LAG-3 inhibitor, and a CTLA-4 inhibitor, such that the subject receives all four.

In an embodiment, the subject has been or will be administered an agent that inhibits poly(ADP-ribose) polymerase (PARP), such that the subject is treated with a TIM-3 inhibitor and a PARP inhibitor.

In an embodiment, the subject has been or will be administered one or more immune checkpoint inhibitors (e.g., a PD-1 inhibitor and/or a LAG-3 inhibitor), such that the subject is treated with a TIM-3 inhibitor, a PARP inhibitor (e.g., niraparib), and one or more immune checkpoint inhibitors. In an embodiment, the subject is administered a TIM-3 inhibitor, a PD-1 inhibitor (e.g., TSR-042), and a PARP inhibitor (e.g., niraparib). In an embodiment, the subject is administered a TIM-3 inhibitor, a PD-1 inhibitor (e.g., TSR-042), a LAG-3 inhibitor, and a PARP inhibitor (e.g., niraparib).

For female patients of childbearing potential, the patient preferably has a negative serum pregnancy test within 72 hours of the date of administration of the first dose of the anti-TIM-3 antibody agent. Female and male patients of childbearing potential also preferably agree to use two reasonable methods of contraception with their partner. In some embodiments, patients agree to use two methods of contraception starting from the screening visit through 150 days after the final dose of study therapy.

The present disclosure provides, in some embodiments, a method of treating cancer in a patient in need thereof, comprising administering one or more compositions delivering an anti-TIM-3 antibody agent in combination with a PD-1 binding agent (e.g., a PD-1 binding agent such as an anti-PD-1 antibody). FIG. 1 shows an exemplary schematic of a combination of an anti-TIM-3 and an anti-PD-1 antibody for enhanced anti-tumor efficacy. In some embodiments, the patient or patient population is receiving a combination therapy comprising administration of an anti-TIM-3 antibody agent and a PD-1 binding agent. In some embodiments, the PD-1 binding agent is nivolumab or pembrolizumab. In embodiments, the PD-1 inhibitor is a PD-1 binding agent (e.g., an antibody, antibody conjugate, or antigen-binding fragment thereof). In embodiments, the PD-1 binding agent is nivolumab, pembrolizumab, TSR-042, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283, MGA012, BI-754091, IBI-308, camrelizumab. mab (HR-301210), BCD-100, JS-001, CX-072, AMP-514/MEDI-0680, AGEN-2034, CS1001, TSR-042, Sym-021, PF-06801591, LZM009, KN-035, AB122, genolimuzumab (CBT-501), AK 104, or GLS-010, or derivatives thereof. In embodiments, the PD-1 inhibitor is a PD-L1 or PD-L2 binding agent (e.g., an antibody, antibody conjugate, or antigen-binding fragment thereof). In embodiments, the PD-1 binding agent is a PD-L1 or PD-L2 binding agent, such as durvalumab, atezolizumab, avelumab, BGB-A333, SHR-1316, FAZ-053, CK-301, or PD-L1 miramolecule, or a derivative thereof.

In some embodiments, a patient or patient population is receiving a combination therapy that includes administration of an anti-TIM-3 antibody agent that includes an immunoglobulin heavy chain variable domain having an amino acid sequence that includes SEQ ID NO:1 or SEQ ID NO:7 and an immunoglobulin light chain variable domain having an amino acid sequence that includes SEQ ID NO:2 or SEQ ID NO:8. In some embodiments, the anti-TIM-3 antibody agent includes an immunoglobulin heavy chain having an amino acid sequence that includes SEQ ID NO:3 and an immunoglobulin light chain having an amino acid sequence that includes SEQ ID NO:4.

In some embodiments, the patient or patient population is receiving a combination therapy that includes administration of a PD-1-binding agent that includes an immunoglobulin heavy chain variable domain having an amino acid sequence that includes SEQ ID NO:11 or SEQ ID NO:17 and an immunoglobulin light chain variable domain having an amino acid sequence that includes SEQ ID NO:12 or SEQ ID NO:18. In some embodiments, including combinations, the PD-1-binding agent includes an immunoglobulin heavy chain having an amino acid sequence that includes SEQ ID NO:13 and an immunoglobulin light chain having an amino acid sequence that includes SEQ ID NO:14.

In some embodiments, the anti-TIM-3 antibody agent (e.g., an anti-TIM-3 antibody) is administered at a dose of 0.1, 1, 3, or 10 mg/kg. In some embodiments, the anti-TIM-3 antibody agent is administered according to a regimen including a dose of 0.1, 1, 3, or 10 mg/kg once every two weeks. In some embodiments, the anti-TIM-3 antibody agent is administered according to a regimen including a dose of 1, 3, or 10 mg/kg once every three weeks.

In some embodiments, the anti-TIM-3 antibody agent is administered according to a regimen including a dose of 1, 3, or 10 mg/kg once every four weeks. In some embodiments, the anti-TIM-3 antibody agent at a fixed dose in the range of about 200 mg to 1,500 mg. In some embodiments, the anti-TIM-3 antibody agent at a fixed dose in the range of about 300 mg to 1,000 mg. In some embodiments, the anti-TIM-3 antibody agent is administered according to a regimen including a fixed dose once every two weeks. In some embodiments, the anti-TIM-3 antibody agent is administered according to a regimen including a fixed dose once every three weeks. In some embodiments, the anti-TIM-3 antibody agent is administered according to a regimen including a fixed dose once every four weeks.

In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody such as TSR-042) is administered at a dose of about 1, 3, or 10 mg/kg. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody such as TSR-042) is administered according to a regimen including a dose of about 1, 3, or 10 mg/kg once every two weeks. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody such as TSR-042) is administered according to a regimen including a dose of about 1, 3, or 10 mg/kg once every three weeks. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody) is administered according to a regimen including a dose of about 1, 3, or 10 mg/kg once every four weeks. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody such as TSR-042) at a dose of about 500 mg. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody such as TSR-042) is administered according to a regimen including a dose of about 500 mg/kg once every two weeks. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody such as TSR-042) is administered according to a regimen including a dose of about 500 mg/kg once every three weeks. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody such as TSR-042) is administered according to a regimen including a dose of about 500 mg/kg once every four weeks. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody such as TSR-042) is administered according to a regimen including a dose of about 1000 mg/kg once every six weeks. In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody such as TSR-042) is administered according to a regimen comprising a first dose of about 500 mg once every three weeks (Q3W) for the first 2-6 (e.g., the first 2, 3, 4, 5, or 6) dosing cycles, and a second dose of about 1000 mg once every six weeks (Q6W) until treatment is discontinued (e.g., due to disease progression, adverse effects, or physician's decision). In some embodiments, the PD-1 binding agent (e.g., an anti-PD-1 antibody such as TSR-042) is administered according to a regimen comprising a first dose of about 500 mg once every three weeks (Q3W) for the first four dosing cycles, and a second dose of about 1000 mg once every six weeks (Q6W) until treatment is discontinued (e.g., due to disease progression, adverse effects, or physician's decision). In embodiments, the PD-1 binding agent is an anti-PD-1 antibody. In an embodiment, the anti-PD-1 binding agent is TSR-042.

In certain methods, the anti-TIM-3 antibody agent can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to) or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) administration of the PD-1-binding agent to a subject in need thereof.
Measurement of tumor response

In some embodiments, the clinical benefit is a complete response ("CR"), partial response ("PR"), or stable disease ("SD"). In some embodiments, the clinical benefit corresponds to at least a SD. In some embodiments, the clinical benefit corresponds to at least a PR. In some embodiments, the clinical benefit corresponds to a CR. In some embodiments, at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of patients achieve a clinical benefit. In some embodiments, at least 5% of patients achieve a clinical benefit. In some embodiments, at least 5% of patients achieve a SD. In some embodiments, at least 5% of patients achieve at least a PR. In some embodiments, at least 5% of patients achieve a CR. In some embodiments, at least 20% of patients achieve a clinical benefit. In some embodiments, at least 20% of patients achieve SD.

In some embodiments, clinical benefit (e.g., SD, PR, and/or CR) is determined according to Response Evaluation Criteria in Solid Tumors (RECIST). In some embodiments, clinical benefit (e.g., SD, PR, and/or CR) is determined according to RECIST guidelines.

In some embodiments, tumor response may be measured, for example, by the RECIST v1.1 guidelines. The guidelines are provided by E. A. Eisenhauer et al., "New response evaluation criteria in solid tumors: Revised RECIST guidelines (version 1.1.)," Eur. J. of Cancer, 45:228-247 (2009), which is incorporated herein by reference in its entirety. The guidelines require an estimate of overall tumor burden at baseline first, which is used as a comparison for subsequent measurements. Tumors may be measured via any imaging system known in the art (e.g., by CT scan or x-ray). Measurable disease is defined by the presence of at least one measurable lesion. In trials in which the primary endpoint is tumor progression (time to progression-free or proportion of progression at fixation date), the protocol must specify whether entry is restricted to those with measurable disease or whether patients with only nonmeasurable disease are also eligible.

If two or more measurable lesions are present at baseline, all lesions, up to a total of five lesions (and a maximum of two lesions per organ) representing all involved organs, should be identified as target lesions and recorded and measured at baseline (this means that if a patient has only one or two involved organ sites, a maximum of two and four lesions will be recorded, respectively).

Target lesions should be selected based on size (lesions with the longest diameter) and should be representative of all involved organs, but should also be lesions that allow reproducible repeated measurements.

Lymph nodes deserve special mention because they are normal anatomical structures that may be visible by imaging even in the absence of tumor involvement. To be defined as measurable and to be identifiable as a target lesion, a pathological node must meet the criteria of a short axis of P15 mm by CT scan. Only the short axis of such a node contributes to the baseline sum. The short axis of a node is the diameter that radiologists typically use to determine whether a node is involved by a solid tumor. The size of a node is usually reported as two dimensions in the plane in which the image is acquired (for CT scans, this plane is almost always the axial plane; for MRI, the acquisition plane may be axial, sagittal, or coronal). The smaller of these measurements is the short axis.

For example, an abdominal node reported as being 20 mm, 30 mm has a short axis of 20 mm and qualifies as a malignant measurable node. In this example, 20 mm should be recorded as the measurement of the node. All other pathological nodes (those with a short axis of P10 mm but <15 mm) should be considered non-target lesions. Nodules with a short axis <10 mm are considered non-pathological and should not be recorded or followed.

The sum of diameters (longest diameter for nonnodal lesions, short axis for nodal lesions) for all target lesions is calculated and reported as the baseline sum diameter. If lymph nodes are included in the sum, only the short axis is added to the sum, as described above. The baseline sum diameter is used as a reference to further characterize any objective tumor regression in measurable dimensions of disease.

All other lesions (or sites of disease), including pathological nodes, should be identified as non-target lesions and these should also be recorded at baseline. Measurements are not required and these lesions should be tracked as "present," "absent," or in rare cases, "overt progression." In addition, multiple non-target lesions involving the same organ may be considered for recording as a single item on the case record form (e.g., "multiple enlarged pelvic lymph nodes" or "multiple liver metastases").

In some embodiments, tumor response can be measured by immune-related RECIST (irRECIST) guidelines, including, for example, immune related Response Criteria (irRC), which measure measurable lesions with at least one dimension of a minimum size of 10 mm (in the longest diameter by CT or MRI scan) for non-nodal lesions, 15 mm or greater for nodal lesions, or at least 20 mm on chest x-ray.

In some embodiments, immune-related response criteria include CR (complete disappearance of all lesions (measurable or non-measurable and no new lesions)); PR (≥50% reduction in tumor burden relative to baseline); SD (not meeting criteria for CR or PR in the absence of PD); or PD (≥25% increase in tumor burden relative to nadir). A detailed description of irRECIST can be found in Bohnsack et al. (2014) ESMO, ABSTRACT 4958 and Nishino et al. (2013) Clin. Cancer Res. 19(14):3936-43.

In some embodiments, tumor response may be assessed by either irRECIST or RECIST version 1.1. In some embodiments, tumor response may be assessed by both irRECIST and RECIST version 1.1.
Pharmacokinetics

Pharmacokinetic data can be obtained by techniques known in the art. Due to the inherent variation in pharmacokinetic and pharmacodynamic parameters of drug metabolism in human subjects, appropriate pharmacokinetic and pharmacodynamic profile components describing a particular composition can vary. Typically, pharmacokinetic and pharmacodynamic profiles are based on the determination of mean parameters in a group of subjects. The group of subjects includes any reasonable number of subjects suitable for determining a representative mean value, e.g., 5 subjects, 10 subjects, 16 subjects, 20 subjects, 25 subjects, 30 subjects, 35 subjects, or more. The mean value is determined by calculating the average of all subject measurements for each parameter measured.

In some embodiments, the patient population includes one or more subjects ("subject population") suffering from metastatic disease.

In some embodiments, the patient population includes one or more subjects suffering from or susceptible to cancer. In some such embodiments, the cancer is non-small cell lung cancer (NSCLC), hepatocellular carcinoma, renal cancer, melanoma, cervical cancer, colorectal cancer, squamous cell carcinoma of the anogenital region (e.g., squamous cell carcinoma of the anus, penis, cervix, vagina, or vulva), head and neck cancer, triple-negative breast cancer, ovarian cancer, or endometrial cancer. In embodiments, the cancer is a solid tumor (e.g., an advanced solid tumor, a metastatic solid tumor, an MSS solid tumor, an MSI-H solid tumor, or a POLE-mutated solid tumor). In embodiments, the cancer is melanoma (e.g., an advanced melanoma, a metastatic melanoma, an MSS melanoma, an MSI-H melanoma, or a POLE-mutated melanoma). In embodiments, the cancer is lung cancer such as NSCLC (e.g., advanced NSCLC, metastatic NSCLC, MSI-H NSCLC, MSS NSCLC, POLE mutated NSCLC, EGFR mutated NSCLC, or ALK translocation NSCLC). In embodiments, the cancer is colorectal cancer (e.g., advanced colorectal cancer, metastatic colorectal cancer, MSS colorectal cancer, MSI-H colorectal cancer, MSI-H colorectal cancer, or POLE mutated colorectal cancer). In some embodiments, the patient population includes (e.g., comprises or consists of) one or more subjects suffering from cancer. For example, in some embodiments, the patient population suffering from cancer may have been previously treated with prior therapy (e.g., radiation and/or chemotherapy).

In some embodiments, the pharmacokinetic parameters may be any parameters suitable for describing the compositions of the present invention.

In some embodiments, the pharmacokinetic parameter may be any parameter suitable for describing a composition of the present invention. For example, in some embodiments, _Cmax is about 1 μg/ml; about 5 μg/ml, about 10 μg/ml, about 15 μg/ml, about 20 μg/ml, about 25 μg/ml, about 30 μg/ml, about 35 μg/ml, about 40 μg/ml, about 45 μg/ml, about 50 μg/ml, about 55 μg/ml, about 60 μg/ml, about 65 μg/ml, about 70 μg/ml, about 75 μg/ml, about 80 μg/ml, about 85 μg/ml, about 90 μg/ml, about 95 μg/ml, about 100 μg/ml, about 150 μg/ml, about 200 μg/ml, about 250 μg/ml, about 300 μg/ml, or any other _Cmax suitable to describe the pharmacokinetic profile of the anti-TIM-3 antibody.

In some embodiments, the _Tmax is, e.g., about 0.5 hours or less, about 1.0 hours or less, about 1.5 hours or less, about 2.0 hours or less, about 2.5 hours or less, or about 3.0 hours or less, or any other _Tmax suitable to describe the pharmacokinetic profile of the anti-TIM-3 antibody.

In general, the AUC described herein is a measure of the area under the curve corresponding to the concentration of an analyte over a selected time period after administration of a dose of a therapeutic agent. In some embodiments, such time period begins at the time of dose administration (e.g., 0 hours after dose administration) and extends to about 2, about 6, about 12, about 36, about 48, about 72, about 168, about 336, about 514, about 682, or more hours after dose administration. In some embodiments, the AUC is achieved between 0 hours and 336 hours after administration of a dose described herein.

AUC _(0-336h) is, for example, about 500 μhr/mL, about 1000 μhr/mL, about 1500 μhr/mL, about 2000 μhr/mL, about 2500 μhr/mL, about 3000 μhr/mL, about 3500 μhr/mL, about 4000 μhr/mL, about 4500 μhr/mL, about 5000 μhr/mL, about 7500 μhr/mL, about 10,000 μhr/mL, about 15,000 μhr/mL, about 20,000 μhr/mL, and the like. The average AUC 0-336h of the anti-TIM-3 antibody concentration-time curve may be about 2500 h*μg/mL, about 25,000 μhr/mL, about 30,000 μhr/mL, about 35,000 μhr/mL, about 40,000 μhr/mL, about 45,000 μhr/mL, about 50,000 μhr/mL, about 65,000 μhr/mL, about 75,000 μhr/mL, about 90,000 μhr/mL, or any other _(0-336h) appropriate to describe the pharmacokinetic profile of the therapeutic agent (e.g., an anti-TIM-3 antibody). In some embodiments, the anti-TIM-3 antibody is administered according to a regimen that has been demonstrated to achieve a mean AUC _0-336h of the anti-TIM-3 antibody concentration-time curve of 2500 h*μg/mL to 50000 h*μg/mL in a patient population.

In some embodiments, the AUC from time 0 to the end of the dosing period is determined (AUC _(0-Tau) ). In some embodiments, the dosing period is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks. In some embodiments, the dosing period is 2 weeks. In some embodiments, the dosing period is 3 weeks.

In some embodiments, the anti-TIM-3 antibody is administered according to a regimen that has been demonstrated to achieve a response rate in a relevant patient population such that 50% to 80% or less of patients exhibit progressive disease 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 weeks after initiation of treatment. In some embodiments, 80% or less of patients exhibit progressive disease at least 10 weeks after initiation of treatment.

In some embodiments, the anti-TIM-3 antibody is administered according to a regimen sufficient to achieve an average TIM-3 receptor occupancy of at least 50% to 90% 1, 2, 3, 4, or 5 days after a single dose of the composition. In some embodiments, administration of the composition delivers sufficient anti-TIM-3 antibody to achieve an average TIM-3 receptor occupancy of at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% 3 days after a single dose of the composition.

In some embodiments, the anti-TIM-3 antibody is administered according to a regimen sufficient to achieve a mean stimulation rate of at least 1 in a functional TIM-3 receptor occupancy assay 3 days after a single dose of the TIM-3 binding agent.

In some embodiments, the anti-TIM-3 antibody is administered according to a regimen sufficient to achieve an average TIM-3 receptor occupancy of at least 75% over a first time period, e.g., about 14 days to about 60 days, from a single dose of the anti-TIM-3 antibody. In some embodiments, the anti-TIM-3 antibody is administered according to a regimen sufficient to achieve an average TIM-3 receptor occupancy of at least 75% over a first time period (e.g., about 15 days to about 60 days; in some embodiments, about 29 days) from a single dose of the anti-TIM-3 antibody.

In some embodiments, the anti-TIM-3 antibody is administered according to a regimen sufficient to achieve an average stimulation rate of at least 1 in a functional TIM-3 receptor occupancy assay over a first time period, e.g., about 14 days to about 60 days, from a single dose of the anti-TIM-3 antibody. In some embodiments, the anti-TIM-3 antibody is administered according to a regimen sufficient to achieve an average stimulation rate of at least 1 in a functional TIM-3 receptor occupancy assay over a first time period (e.g., about 15 days to about 60 days, in some embodiments about 29 days) from a first dose of the anti-TIM-3 antibody.

The following examples are provided to illustrate, but not to limit, the claimed invention. Example 1 Combinatorial blockade of TIM-3 and PD-1 in a mouse model system

The effect of TIM-3 and PD-1 blockade in a mouse T cell exhaustion assay was examined (Burkhart et al., Int Immunol. 1999;11:1625-1634). In this system, in vitro stimulation of mouse CD4+ T cell receptor transgenic T cells with a superagonist modified peptide ligand results in an exhausted phenotype characterized by increased expression of PD-1 and TIM-3 (Figure 2A). As shown in Figure 2B, the combination of anti-PD-1 and anti-TIM-3 antibodies enhanced IFNγ production in this system more effectively than either agent alone.
Example 2 In vivo efficacy study of the combination of TSR-042 and TSR-022

In addition to assessing the combinatorial effect of targeting PD-1 and TIM-3 in vitro, the combination was also tested in an animal model of lung cancer. A humanized mouse tumor model consisting of A549 human lung cancer cells ( ^5x106 cells per mouse) implanted in huNOG-EXL mice was used. Neonatal-derived CD34+ hematopoietic stem cells were implanted into the mice, and the mice were treated with monoclonal blocking antibodies targeting PD-1 (TSR-042) and TIM-3 (TSR-022). Here, we show that the combination of anti-PD-1 and anti-TIM-3 has beneficial antitumor effects compared to either agent alone (Figure 3).
Example 3 Exemplary Dosing Regimens for TIM-3 Binding Agents

This example describes a multicenter, open-label, first-in-human, Phase 1 study evaluating a TIM-3 binder (anti-TIM-3 antibody) in patients with tumors. Specifically, dosing provides benefit in patients with advanced solid tumors treated with a particular TIM-3 binder. The TIM-3 binder described in this study (TSR-022) comprises a humanized monoclonal anti-TIM-3 antibody comprising a heavy chain having an amino acid sequence comprising SEQ ID NO:3 and a light chain having an amino acid sequence comprising SEQ ID NO:4. This anti-TIM-3 antibody utilizes the human IGHG4*01 heavy chain gene and the human IGKC*01 light chain gene as a scaffold. Additionally, there is a single Ser to Pro point mutation at the canonical S228 position within the hinge region of the IgG4 heavy chain.

Included patients had histologically or cytologically proven advanced (unresectable) or metastatic solid tumors and had disease progression following treatment with available therapies known to confer clinical benefit or were intolerant to other known treatments.

The study includes several parts: dose escalation and cohort expansion. Part 1a (dose escalation) of the study is intended to evaluate, among other things, the safety, PK, and PDy profile, tolerability, and anticancer efficacy of the anti-TIM-3 antibody. A modified 3+3 design was used to escalate doses of the TIM-3 antibody to 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg, 3 mg/kg, and 10 mg/kg every 2 weeks (Q2W) and higher, not to exceed 20 mg/kg. Dose escalation continued to 1.0 mg/kg Q2W, and the MTD was still not identified. Part 1a could also include testing of a "flat" dose, i.e., a specific fixed number of milligrams of antibody (as opposed to weight-based dosing mg/kg). The flat dose could range from 200 mg to 1500 mg of the anti-TIM-3 antibody. Part 1b of the study (combination with PD1 dose escalation cohort) is specifically intended to evaluate the safety, PK, and PDy profile, tolerability, and anti-cancer efficacy of combinations of anti-TIM-3 and anti-PD-1 antibodies, where the anti-TIM-3 antibodies are administered as dose escalations, including combinations of 1.0 mg/kg, 3 mg/kg, and 10 mg/kg or more of each anti-TIM-3 (with the dose of anti-TIM-3 not exceeding the MTD defined in Part 1a of the study) once every two weeks (Q2W) or once every three weeks (Q3W) in combination with anti-PD-1 (exemplary anti-PD-1 antibodies are a humanized monoclonal anti-PD-1 antibody comprising a heavy chain having an amino acid sequence comprising SEQ ID NO: 13 and a light chain having an amino acid sequence comprising SEQ ID NO: 14, nivolumab, or pembrolizumab). Anti-PD-1 antibodies can be administered at the approved doses and schedules of marketed drugs, as well as on a body weight basis at doses of 3 or 10 mg/kg Q2W or Q3W, or on a flat dose basis of 500 mg antibody Q2W or Q3W, using a modified 3+3 design.

Primary endpoints include determining the safety and tolerability of TSR-022 by Common Terminology Criteria for Adverse Events (CTCAE v4) and determining the recommended phase 2 dose (RP2D) and combination with anti-PD-1 antibodies. Secondary endpoints include pharmacokinetics (PK), response rate, duration of response, disease control rate, progression-free survival, overall survival, and immunogenicity. Exploratory endpoints include pharmacodynamics.

Figure 4A shows the doses used for TSR-022 monotherapy in the Part 1a dose escalation study. As of October 27, 38 patients with advanced cancer had been enrolled in the dose escalation study. Patients were administered doses of 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, and 10 mg/kg.

Adult patients with advanced or metastatic solid tumors, with disease progression or tolerability after treatment with available therapies, and with adequate organ function and ECOG performance status were treated. Prior therapy with immune checkpoint inhibitors was permitted. A summary of patient demographic characteristics is shown in Figure 5 for the 38 patients enrolled. In Part 1a, there were 21 male and 17 female patients. The mean age was 60.1 years (SD = 13.5), median 61.0 years (min = 25; max = 85). The mean number of prior lines of therapy was 3.2 (SD = 2.3), median 2.0 (min = 1; max = 10). Ten patients had an ECOG performance status of 0 and 28 had an ECOG performance status of 1. Tumor sites included colon, skin, ovary, breast, brain, head and neck, testis, pleura, lung, rectum, thyroid, liver, or esophagus.

After patients received their first dose of TSR-022 at various levels (0.03-10 mg/kg), serum TSR-022 concentrations were monitored for 2 weeks to characterize the pharmacokinetic (PK) behavior. Figure 6A shows the serum concentration vs. time profiles of the pretreatment groups in Part 1. TSR-022 demonstrated linear PK behavior at the doses tested, 0.03-10 mg/kg.

Figure 6B shows TIM-3 occupancy on circulating monocytes measured by flow cytometry from whole blood samples from patients treated with anti-TIM-3. Receptor occupancy on peripheral monocytes was shown to correlate with TSR-022 exposure.

TIM-3 receptor occupancy (RO) on circulating CD14 ⁺ monocytes by TSR-022 was measured by flow cytometry. Briefly, whole blood samples from patients treated with TSR-022 were stained with a non-competitive anti-TIM-3 antibody, anti-CD14 (representing total TIM-3) and a competitive anti-TIM-3 antibody (representing unbound or free TIM-3). TIM-3 occupancy by infused TSR-022 was estimated as the ratio of free TIM-3 on CD14+ cells to total TIM-3 on CD14+ cells. A decrease in the ratio indicates an increase in TSR-022-bound TIM-3 receptors. To measure binding in the RO assay, whole blood was collected from patients at baseline (pre-dose on day 1), 48 hours after the first dose (day 3), and before the second dose (pre-dose on day 15) on a Q2W schedule. In the subset of patients who did not receive a second dose, additional samples were collected on days 22 and 29 after the first dose. Samples for occupancy measurements on the Q3W schedule were collected as follows: pre-dose on day 1, days 5, 15, and 22. Controls included healthy donor samples saturated with ex vivo TSR-022 ("Saturated") and controls lacking detection antibody ("Background").

Figures 7A-7C show receptor occupancy studies of anti-TIM-3 antibody (TSR-022) administered at doses of 1 mg/kg (Figure 7A), 3 mg/kg (Figure 7B), and 10 mg/kg (Figure 7C) once every two weeks (Q2W), respectively. Pre-samples were pre-dosed and occupancy was measured after a single dose on day 1. Occupancy (free TIM-3:total TIM-3) was determined at various time points (e.g., time points could include days 1, 3, 15, 22, and 29). Receptor occupancy was maximal on day 3 across each dose of TSR-022. Maximal occupancy was maintained through day 29 at 3 mg/kg, with comparable results across the days in the available data at 10 mg/kg.

Figure 8 provides an overview of the dosages administered to patients (0.03-10 mg/kg) and duration of treatment during the Part 1a study.

The best response observed in efficacy-evaluable patients (e.g., patients who received at least two doses and had at least one post-baseline assessment or who discontinued treatment due to clinical progression before a post-baseline tumor assessment) was also evaluated. Stable disease (5/25 patients) and partial response (1/25 patients at 10 mg/kg) were observed as best responses in patients with rectal, thyroid, neuroendocrine, or head and neck cancer, or soft tissue sarcoma.

Figure 9 shows a brain scan from a patient with a partial response at the 10/mg level. The patient is 42 years old and has leiomyosarcoma that has metastasized to the lungs and kidneys (kidney biopsy confirmed leiomyosarcoma: PTEN splice site, MYC amplification, ATRX mutation, CD36 mutation, RB loss, p53 loss; low mutational burden). The patient received 3 doses of TSR-022 at 10 mg/kg prior to restaging imaging. In addition, the patient received gemcitabine and docetaxel for 5 months and showed progression prior to entering this study. Although confirmatory imaging is pending, there appears to be a 32% tumor reduction at the 10 mg/kg dose level and treatment is ongoing.

This study demonstrated that TSR-022 monotherapy was well tolerated across multiple dose levels.

Part 2 of the study is intended to, inter alia, evaluate the safety and tolerability, PK, and PDy profiles, and anti-cancer efficacy of (i) an anti-TIM-3 antibody in a fixed dose Q2W or Q3W, or (ii) an anti-TIM-3 antibody in a fixed dose Q2W or Q3W in combination with an anti-PD-1 antibody in a weight-based or fixed dose as set forth above. The anti-PD-1 antibody may be administered according to a regimen of 500 mg once every 3 weeks (Q3W) for the first treatment cycle (e.g., 500 mg Q3W for four treatment cycles), followed by 1000 mg once every 6 weeks (Q6W) until treatment is discontinued (e.g., due to disease progression).

A flat dose of about 100 mg to 1500 mg of an anti-TIM-3 antibody can be administered as monotherapy or in combination therapy. For example, a dose of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg of an anti-TIM-3 antibody can be administered Q1W, Q2W, Q3W, Q4W, Q5W, or Q6W as monotherapy or in combination with an anti-PD-1 antibody administered 500 mg Q3W for four treatment cycles, then 1000 mg Q6W until treatment is discontinued (e.g., due to disease progression). In embodiments, an anti-TIM-3 antibody at a dose of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg may be administered Q2W or Q3W as monotherapy or in combination with an anti-PD-1 antibody administered at 500 mg Q3W for four treatment cycles, then 1000 mg Q6W until treatment is discontinued (e.g., due to disease progression). Anti-TIM-3 antibodies at doses of 100 mg, 200 mg, 300 mg, 500 mg, 800 mg, 1000 mg, or 1200 mg can be administered as monotherapy once a week (Q1W), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), or once every three weeks (Q6W). Anti-TIM-3 antibodies at doses of 100 mg, 200 mg, 300 mg, 500 mg, 800 mg, 1000 mg, or 1200 mg can be administered as monotherapy once every two weeks (Q2W) or once every three weeks (Q3W).

Receptor occupancy studies were performed based on a flat dose of 100 mg of anti-TIM-3 antibody administered once every three weeks (Q3W). Pre-samples were taken pre-dose and occupancy was measured after the single dose on day 1. As shown in Figure 10, peripheral target coverage is achieved at 100 mg for the duration of the dosing interval. Furthermore, receptor occupancy at 100 mg Q3W is comparable to 3 mg/kg Q2W (Figure 7B).

Receptor occupancy studies following administration of a flat 300 mg dose of an exemplary anti-TIM-3 antibody (TSR-022) in combination with a flat 500 mg dose of an exemplary anti-PD-1 antibody (TSR-042) were also performed according to the methods described herein. The data are shown in FIG. 11. A second dose of TSR-022 was administered on day 22, and RO samples were collected prior to the second dose. Using a flat 300 mg dose of TSR-022, high RO can be maintained over the measured time period.

Figure 12 combines mean receptor occupancy data for an exemplary anti-TIM-3 antibody (TSR-022) at doses of 1 mg/kg, 3 mg/kg, 10 mg/kg, as well as flat doses of 100 mg, 300 mg, and 1200 mg. This figure shows that high occupancy (free TIM-3:total TIM-3) can be achieved with various doses of TSR-022, as measured over a range of days.

These monotherapy and combination regimens will be tested in specific tumor types, which may include anti-PD1/L1-treated melanoma, anti-PD1/L1-treated NSCLC, colorectal cancer, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, and/or breast cancer. Figure 4B shows an overview of the expansion cohort study in part 2.
Equivalent

In this specification, the articles "a" and "an" in the specification and claims should be understood to include plural referents unless clearly indicated to the contrary. A claim or description containing "or" between one or more members of a group is considered to be satisfied if one, more than one, or all of the group members are present, used, or otherwise relevant in a given product or process, unless indicated to the contrary or otherwise clear from the context. The invention includes embodiments in which exactly one member of a group is present, used, or otherwise relevant in a given product or process. The invention also includes embodiments in which two or more, or all, group members are present, used, or otherwise relevant in a given product or process. Furthermore, it is understood that the invention encompasses all variations, combinations, and permutations, and that one or more limitations, elements, clauses, descriptive terms, etc. from one or more of the claims listed may be introduced into another claim that is dependent on (or related to) the same base claim (or any other claim that is related to) unless otherwise indicated or is otherwise apparent to one of ordinary skill in the art that a contradiction or inconsistency would result. Where elements are presented as a list (e.g., in a Markush group or similar format), it is to be understood that each subgroup of elements is also disclosed and that any element may be removed from the group. In general, where the invention, or aspects of the invention, are referred to as including certain elements, features, etc., it should be understood that a particular embodiment of the invention or aspect of the invention consists or consists essentially of such elements, features, etc. For clarity, such embodiments have not been specifically described herein in every instance. It should also be understood that any embodiment or aspect of the invention may be expressly excluded from the claims, regardless of whether a specific exclusion is recited herein. Publications, websites, and other reference materials referenced herein to describe the background of the invention and to provide further details regarding its practice are incorporated herein by reference.

Claims (30)

A composition for use in treating cancer in humans, the composition comprising a T cell immunoglobulin and mucin protein 3 (TIM-3) binding agent, the TIM-3 binding agent being administered in a flat dose of about 100 mg to about 1200 mg, the TIM-3 binding agent comprising an antibody, antibody conjugate, or antigen-binding fragment thereof, and comprising a heavy chain variable region having the three CDR sequences of SEQ ID NO:21 (HCDR1), SEQ ID NO:22 (HCDR2), and SEQ ID NO:23 (HCDR3), and a light chain variable region having the three CDR sequences of SEQ ID NO:24 (LCDR1), SEQ ID NO:25 (LCDR2), and SEQ ID NO:26 (LCDR3). and the TIM-3-binding agent is administered together with an anti-PD-1 antibody. ,Composition. The composition of claim 1, wherein the TIM-3 binding agent is administered in a flat dose of about 100 mg to about 500 mg. The composition of claim 2, wherein the TIM-3 binding agent is administered in a flat dose of about 100 mg to about 300 mg. The composition of claim 2, wherein the TIM-3 binding agent is administered in a flat dose of about 200 mg to about 500 mg. The composition according to any one of claims 1 to 4, characterized in that the TIM-3 binding agent is administered once every three weeks (Q3W). The composition according to any one of claims 1 to 5, wherein the TIM-3 binding agent is an antibody. The composition of claim 6, wherein the TIM-3 binding agent comprises an immunoglobulin heavy chain variable domain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO:1 or SEQ ID NO:7, and/or an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO:2 or SEQ ID NO:8. The composition of claim 7, wherein the TIM-3 binding agent comprises an immunoglobulin heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:7, and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:8. The composition of claim 7 or 8, wherein the TIM-3 binding agent is an immunoglobulin G4 (IgG4) humanized monoclonal antibody. The composition of any one of claims 7 to 9, wherein the TIM-3 binding agent comprises an immunoglobulin heavy chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO:3, and/or an immunoglobulin light chain comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO:4. The composition of claim 10, wherein the TIM-3 binding agent comprises an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO:3 and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO:4. The composition according to any one of claims 1 to 11, characterized in that the composition is administered intravenously, optionally by intravenous infusion. The composition according to any one of claims 1 to 12, wherein the cancer is a solid tumor, optionally an advanced stage solid tumor. The cancer is
i. Cancer with high tumor mutation burden (TMB);
ii. Cancers that are microsatellite stable (MSS);
iii. Cancers characterized by microsatellite instability;
iv. Cancers with microsatellite instability high status (MSI-H);
v. Cancers with microsatellite instability low status (MSI-L);
vi. Cancer with high TMB and MSI-H;
vii. Cancer with high TMB and MSI-L or MSS;
viii. Cancers with defective DNA mismatch repair systems;
ix. Cancers with defects in DNA mismatch repair genes;
x. hypermutable cancer;
xi. Cancers containing mutations in polymerase delta (POLD);
xii. Cancers containing mutations in polymerase epsilon (POLE);
xiii. Cancer with homology directed repair deficiency/homology directed repair deficiency (HRD);
xiv. Adenocarcinoma, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, testicular cancer, primary peritoneal cancer, colon cancer, colorectal cancer, stomach cancer, small intestine cancer, squamous cell carcinoma of the anus, squamous cell carcinoma of the penis, squamous cell carcinoma of the cervix, squamous cell carcinoma of the vagina, squamous cell carcinoma of the vulva, soft tissue sarcoma, melanoma, renal cell carcinoma, lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung, stomach cancer, bladder cancer, gallbladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary gland cancer xv. cancer of the esophagus, head and neck, squamous cell carcinoma of the head and neck, prostate, pancreatic cancer, mesothelioma, Merkel cell carcinoma, sarcoma, glioblastoma, blood cancer, multiple myeloma, B cell lymphoma, T cell lymphoma, Hodgkin lymphoma/primary mediastinal B cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin lymphoma, neuroblastoma, CNS tumors, diffuse intrinsic pontine glioma (DIPG), Ewing sarcoma, embryonal rhabdomyosarcoma, osteosarcoma, or Wilms'tumor; or xv. The composition of any one of claims 1 to 13, wherein the cancer is MSS or MSI-L, characterized by microsatellite instability, MSI-H, has high TMB, has high TMB and MSS or MSI-L, has high TMB and MSI-H, has a defective DNA mismatch repair system, has a defect in a DNA mismatch repair gene, is a hypermutable cancer, is an HRD cancer, comprises a mutation in polymerase delta (POLD) or comprises a mutation in polymerase epsilon (POLE), xiv. The composition of claim 14, wherein the cancer is lung cancer. The composition of claim 14, wherein the cancer is non-small cell lung cancer. The composition of claim 14, wherein the cancer is melanoma. The composition according to any one of claims 1 to 13, wherein the cancer is hepatocellular carcinoma. The composition of any one of claims 1 to 18 , wherein the human has been or will be administered an immune checkpoint inhibitor or an agent that inhibits poly(ADP-ribose) polymerase (PARP). The composition of any one of claims 1 to 19 , wherein the human is resistant or refractory to treatment with a PD-1 inhibitor. 21. The composition of any one of claims 1 to 20, wherein the human has previously been treated with one or more different cancer modalities, optionally one or more of surgery, radiation therapy, chemotherapy, or immunotherapy. The composition of any one of claims 1-21, wherein the TIM-3-binding agent is administered prior to administration of the anti-PD-1 antibody. 23. The composition of claim 22, wherein the TIM-3-binding agent is administered 30 minutes prior to administration of the anti-PD-1 antibody. 23. The composition of claim 22, wherein the TIM-3-binding agent is administered 45 minutes prior to administration of the anti-PD-1 antibody. The composition of any one of claims 1 to 24, wherein the anti-PD-1 antibody is nivolumab or pembrolizumab. The composition of any one of claims 1 to 24, wherein the anti-PD-1 antibody comprises a heavy chain comprising SEQ ID NO: 13 and a light chain comprising SEQ ID NO: 14. 27. The composition of claim 26, wherein the anti-PD-1 antibody is administered in a flat dose of 500 mg. The composition of claim 26 or 27, wherein the anti-PD-1 antibody is administered once every three weeks. The composition of any one of claims 1-28, wherein the TIM-3-binding agent is administered together with the anti-PD-1 antibody and a chemotherapeutic agent. The composition of claim 29, wherein the TIM-3-binding agent is administered prior to administration of the chemotherapeutic agent.